TW201000128A - Novel formulation - Google Patents

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TW201000128A
TW201000128A TW098116588A TW98116588A TW201000128A TW 201000128 A TW201000128 A TW 201000128A TW 098116588 A TW098116588 A TW 098116588A TW 98116588 A TW98116588 A TW 98116588A TW 201000128 A TW201000128 A TW 201000128A
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Michael Adler
Hanns-Christian Mahler
Christine Wurth
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Hoffmann La Roche
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    • C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
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Abstract

The present invention relates to a pharmaceutical formulation of an antibody against OX40L, a process for the preparation and uses of the formulation.

Description

201000128 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種抗OX40L抗體的醫藥調配物、該調配 物之製備方法及用途。 【發明内容】 • 在第一態樣中，本發明係關於一種醫藥調配物，其包 .含： 1-200 mg/mL之抗體； ❹ 1-100 mM之緩衝劑； 0.001-1%之表面活性劑； (a) 10-500 mM穩定劑；或 (b) 10-5 00 mM穩定劑及5-500 mM張力劑；或 (c) 5-500 mM張力劑； pH處於4.0至7.0之範圍内， 其中該抗體係抗0X40配體之抗體。 本發明調配物可呈液體形式、凍乾形式或呈自凍乾形式 Q 重構之液體形式。 抗 OX40L 抗體係自（例如）WO 95/12673、WO 95/21915 及 WO 99/15200已知。已對其在各種疾病模型中的消炎作用 進行了研究。可結合至OX40L之市售抗體的實例係可自 % MBL國際公司購得之TAG-34。 抗OX40L之實例性抗體闡述於WO 2006/029879中且包括 特徵在於以下之抗體：該等抗體含有來自人類來源之Fc部 分，可以100 ng之抗體濃度結合至OX40L及變性OX40L(以 西方墨點法（Western Blot))。該等抗體可結合至與單株抗 140095.doc 201000128 體LC.001結合之抗原決定部位相同的OX40L多肽抗原決定 部位上。該等抗體係（例如）LC.001、LC.033及LC.060。該 等抗體較佳屬於人類IgGl型（野生型）或不會結合人類補體 因子Clq及/或NK細胞上之人類Fey受體。 在一個實施例中，本發明提供一種調配物，其包含可結 合至OX40L之抗體，該抗體之特徵在於包含可變輕鏈及可 變重鏈，其特徵在於該可變重鏈包含CDR1、CDR2及 CDR3 ’且特徵在於CDR3係選自SEQ ID NO: 33-38。尤佳 者為 CDR1係選自 SEQ ID NO: 21-25，CDR2係選自 SEQ ID NO: 26-32且 CDR3係選自 SEQ ID NO: 33-38。 該抗體之特徵較佳在於包含可變輕鏈及可變重鏈，其特 徵在於該可變輕鏈包含CDR1、CDR2及CDR3，且特徵在 於CDR3係選自SEQ ID NO: 51-57。尤佳者為CDR1係選自 SEQ ID NO: 39-44號，CDR2係選自 SEQ ID NO: 45-50且 CDR3係選自 SEQ ID NO: 51-57。 該抗體之特徵較佳在於包含可變重鏈及可變輕鏈，其特 徵在於該可變重鏈包含CDR1、CDR2及CDR3，且特徵在 於重鏈CDR3係選自SEQ ID NO: 33-38且輕鏈CDR3係選自 SEQ ID NO: 51-57。尤佳者為可變重鏈包含選自SEQ ID NO: 21-25 之 CDR1、選自 SEq ID NO: 26-32 之 CDR2 及選自 SEQ ID NO: 33-38之CDR3且可變輕鏈包含選自SEQ ID NO: 39-44 之 CDR1、選自 SEq ID NO: 45-50 之 CDR2 及選自 SEQ ID NO: 51_57之 CDR3。 所有CDR彼此獨立地經選擇，但當然以使抗體可結合至 140095.doc 201000128 OX40L之方式選擇。因此，可組合同一 LC抗體之輕鏈及重 鏈CDR或可組合LC.001之輕鏈CDR與LC.001、LC.059或 LC.063之重鏈CDR。各個鏈上之CDR係由架構胺基酸隔 開。 該抗體之特徵較佳在於，該抗體包含獨立選自由下列組 成之群之CDR : a) 胺基酸序列SEQ ID ΝΟ:1之輕鏈（VL)可變CDR及SEQ ID NO:2之重鏈（VH)可變CDR ; b) 胺基酸序列SEQ ID NO:3之輕鏈可變CDR及SEQ ID NO:4 之重鏈可變CDR ; c) 胺基酸序列SEQ ID NO:5之輕鏈可變CDR及SEQ ID NO:6 之重鏈可變CDR ; d) 胺基酸序列SEQ ID NO:7之輕鏈可變CDR及SEQ ID NO:8 之重鏈可變CDR ; e) 胺基酸序列SEQ ID NO:9之輕鏈可變CDR及SEQ ID NO:10之重鏈可變CDR ; f) 胺基酸序列SEQ ID NO:ll或16之輕鏈可變CDR及SEQ ID NO:12之重鏈可變CDR ; g) 由胺基酸序列SEQ ID NO:l定義之輕鏈（VL)可變結構域 及由3£(^1〇>^0:17定義之重鏈（¥1^可變結構域； h) 由胺基酸序列SEQ ID NO: 18定義之輕鏈可變結構域及由 SEQIDNO:19定義之重鏈可變結構域； i) 由胺基酸序列SEQ ID ΝΟ:1定義之輕鏈可變結構域及由 SEQIDNO:20定義之重鏈可變結構域； 140095.doc 201000128 或其OX40L結合片段。 該抗體之特徵較佳在於該抗體包含獨立地選自由以下組 成之群之可變區： a) 由胺基酸序列SEQ ID ΝΟ:1定義之輕鏈（Vl)可變結構域 及由SEQIDNO:2定義之重鏈（VH)可變結構域； b) 由胺基酸序列SEQ ID ΝΟ··3定義之輕鏈可變結構域及由 SEQ ID NO:4定義之重鏈可變結構域； c) 由胺基酸序列SEQ ID NO :5定義之輕鏈可變結構域及由 SEQ ID NO:6定義之重鏈可變結構域； d)由胺基酸序列SEQ ID NO:7定義之輕鏈可變結構域及由 SEQIDNO:8定義之重鍵可變結構域； e) 由胺基酸序列SEQ ID NO:9定義之輕鏈可變結構域及由 SEQIDNO:10定義之重鏈可變結構域； f) 由胺基酸序列SEQ ID ΝΟ··11或16定義之輕鏈可變結構域 及由SEQIDNO:12定義之重鏈可變結構域； g) 由胺基酸序列SEQ ID ΝΟ:1定義之輕鏈（Vl)可變結構域 及由SEQ ID NO:17定義之重鍵（VH)可變结構域· h) 由胺基酸序列SEQ ID NO:18定義之輕鏈可變結構域及由 SEQIDNO:19定義之重鏈可變結構域； i) 由胺基酸序列SEQ ID ΝΟ:1定義之輕鏈可變結構域及由 SEQIDNO:20定義之重鏈可變結構域； 或其OX40L結合片段。 該抗體之特徵較佳在於’人類輕鏈可變區包含獨立地選 自由SEQ ID NO:l、3、5、7、9、U、16及18組成之群的 140095.doc 201000128 胺基酸序列。 該抗體之特徵較佳在於，人類重鏈可變區包含獨立地選 自由 SEQ ID NO:2、4、6、8、10、12、17、19 及 20 組成之 群的胺基酸序列。 重鏈及輕鏈之CDR區示於SEQ ID NO:21-38及39-57中。 該抗體之特徵較佳在於，該抗體包含由胺基酸序列SEQ ID ΝΟ:1定義之輕鏈可變結構域及由SEQ ID NO:2、17或20 定義之重鏈可變結構域。 該抗體之特徵較佳在於，人類重鏈恆定區包含獨立地選 自由SEQ ID NO:14及15或SEQ ID NO:58之重鏈恆定區組 成之群的胺基酸序列。 該抗體之特徵較佳在於，該抗體包含SEQ ID NO: 13之κ 輕鏈恆定區或SEQ ID NO:61、65或69之輕鏈恆定區。 較佳地，本發明抗體之特徵在於可結合至OX40L且屬於 人類IgGl類別（野生型）且包含γ重鏈SEQ ID NO:58、62或 66。尤佳者係包含以下之抗體： a) y 重鏈 SEQ ID NO:58 及 κ 輕鏈 SEQ ID NO:61， b) Y重鏈 SEQ ID NO:62及 κ輕鏈 SEQ ID NO:65，或 。）7重鏈8丑(^10 1^0:66及1<:輕鏈8丑(^10 1^0:69。 本發明又一實施例係包含可結合至OX40L之抗體的調配 物，其特徵在於其由細胞系hu-Mab<hOX40L>LC.001、hu-Mab <hOX40L>LC.005 、hu-Mab<hOX40L>LC.010 、hu-Mab <hOX40L>LC.019 、hu-Mab<hOX40L>LC.029 或 hu-Mab <hOX40L>LC.033產生，如 WO 2006/029879中所述。 140095.doc 201000128 抗體較佳係嵌合人類或人源化抗體。 本發明抗體之特徵較佳在於，其在BIAcore分析中與 OX40L結合之KD值低於1(Τ8 M(10·12至1(Γ8 M)，更佳者係 KD在1〇_12至1〇_9 Μ範圍内。201000128 VI. Description of the Invention: [Technical Field] The present invention relates to a pharmaceutical formulation of an anti-OX40L antibody, a preparation method and use of the formulation. SUMMARY OF THE INVENTION In a first aspect, the present invention relates to a pharmaceutical formulation comprising: 1-200 mg/mL of antibody; ❹ 1-100 mM buffer; 0.001-1% of surface An active agent; (a) 10-500 mM stabilizer; or (b) 10-5 00 mM stabilizer and 5-500 mM tonicity agent; or (c) 5-500 mM tonicity agent; pH in the range of 4.0 to 7.0 Within the antibody, wherein the anti-system is anti-Ox40 ligand. The formulations of the present invention may be in liquid form, in lyophilized form or in liquid form reconstituted from lyophilized form Q. Anti-OX40L anti-systems are known, for example, from WO 95/12673, WO 95/21915 and WO 99/15200. Its anti-inflammatory effects in various disease models have been studied. An example of a commercially available antibody that can be conjugated to OX40L is TAG-34 available from % MBL International. Exemplary antibodies against OX40L are set forth in WO 2006/029879 and include antibodies characterized in that they contain an Fc portion derived from human origin and can bind to OX40L and denatured OX40L at an antibody concentration of 100 ng (by Western blotting) (Western Blot)). The antibodies bind to the same OX40L polypeptide epitope as the epitope that binds to the individual strain 140095.doc 201000128, LC.001. Such anti-systems are for example LC.001, LC.033 and LC.060. Preferably, the antibodies belong to human IgGl type (wild type) or do not bind to human complement factor Clq and/or human Fey receptors on NK cells. In one embodiment, the invention provides a formulation comprising an antibody that binds to OX40L, the antibody comprising a variable light chain and a variable heavy chain, characterized in that the variable heavy chain comprises CDR1, CDR2 And CDR3' and characterized in that the CDR3 is selected from the group consisting of SEQ ID NOs: 33-38. More preferably, the CDR1 is selected from the group consisting of SEQ ID NOs: 21-25, the CDR2 is selected from SEQ ID NOs: 26-32 and the CDR3 is selected from SEQ ID NOs: 33-38. Preferably, the antibody comprises a variable light chain and a variable heavy chain, characterized in that the variable light chain comprises CDR1, CDR2 and CDR3 and is characterized in that the CDR3 is selected from the group consisting of SEQ ID NOs: 51-57. More preferably, the CDR1 is selected from the group consisting of SEQ ID NO: 39-44, the CDR2 is selected from SEQ ID NOS: 45-50 and the CDR3 is selected from SEQ ID NO: 51-57. Preferably, the antibody comprises a variable heavy chain and a variable light chain, characterized in that the variable heavy chain comprises CDR1, CDR2 and CDR3, and characterized in that the heavy chain CDR3 is selected from the group consisting of SEQ ID NOs: 33-38 and The light chain CDR3 is selected from the group consisting of SEQ ID NOs: 51-57. More preferably, the variable heavy chain comprises a CDR selected from the group consisting of SEQ ID NOs: 21-25, a CDR2 selected from the group consisting of SEq ID NO: 26-32, and a CDR3 selected from the group consisting of SEQ ID NOs: 33-38 and comprising a variable light chain comprising CDR1 selected from SEQ ID NOS: 39-44, CDR2 selected from SEq ID NO: 45-50, and CDR3 selected from SEQ ID NO: 51-57. All CDRs were selected independently of each other, but were of course selected in such a way that the antibody could bind to 140095.doc 201000128 OX40L. Thus, the light and heavy chain CDRs of the same LC antibody can be combined or the light chain CDRs of LC.001 can be combined with the heavy chain CDRs of LC.001, LC.059 or LC.063. The CDRs on each chain are separated by an architectural amino acid. Preferably, the antibody is characterized in that the antibody comprises a CDR independently selected from the group consisting of: a) a light chain (VL) variable CDR of the amino acid sequence SEQ ID: 1 and a heavy chain of SEQ ID NO: (VH) variable CDR; b) amino acid sequence SEQ ID NO: 3 light chain variable CDR and SEQ ID NO: 4 heavy chain variable CDR; c) amino acid sequence SEQ ID NO: 5 light a chain variable CDR and a heavy chain variable CDR of SEQ ID NO: 6; d) an amino acid sequence SEQ ID NO: 7 light chain variable CDR and SEQ ID NO: 8 heavy chain variable CDR; e) amine The light chain variable CDR of SEQ ID NO: 9 and the heavy chain variable CDR of SEQ ID NO: 10; f) the amino acid sequence SEQ ID NO: 11 or 16 of the light chain variable CDR and SEQ ID NO a heavy chain variable CDR of 12; g) a light chain (VL) variable domain defined by the amino acid sequence SEQ ID NO: 1 and a heavy chain defined by 3 £(^1〇>^0:17 (¥1^variable domain; h) a light chain variable domain defined by the amino acid sequence SEQ ID NO: 18 and a heavy chain variable domain defined by SEQ ID NO: 19; i) from an amino acid sequence a light chain variable domain as defined by SEQ ID NO: 1 and a heavy chain variable domain defined by SEQ ID NO: 20; 140095.doc 201000128 or O X40L binds to the fragment. Preferably, the antibody is characterized in that the antibody comprises a variable region independently selected from the group consisting of: a) a light chain (V1) variable domain defined by the amino acid sequence SEQ ID ΝΟ: 1 and by SEQ ID NO: 2 defined heavy chain (VH) variable domain; b) a light chain variable domain defined by the amino acid sequence SEQ ID ΝΟ··3 and a heavy chain variable domain defined by SEQ ID NO: 4; c) a light chain variable domain as defined by the amino acid sequence SEQ ID NO: 5 and a heavy chain variable domain defined by SEQ ID NO: 6; d) defined by the amino acid sequence SEQ ID NO: a light chain variable domain and a heavy bond variable domain defined by SEQ ID NO: 8; e) a light chain variable domain defined by the amino acid sequence SEQ ID NO: 9 and a heavy chain defined by SEQ ID NO: a variable domain; f) a light chain variable domain defined by the amino acid sequence SEQ ID ··11 or 16 and a heavy chain variable domain defined by SEQ ID NO: 12; g) from the amino acid sequence SEQ ID ΝΟ: 1 defined light chain (Vl) variable domain and heavy bond (VH) variable domain defined by SEQ ID NO: 17 h) light chain defined by amino acid sequence SEQ ID NO: 18 Variable domain and a heavy chain variable domain as defined by SEQ ID NO: 19; i) a light chain variable domain defined by the amino acid sequence SEQ ID ΝΟ: 1 and a heavy chain variable domain defined by SEQ ID NO: 20; or OX40L thereof Combine the fragments. Preferably, the antibody is characterized in that the human light chain variable region comprises a 140095.doc 201000128 amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 3, 5, 7, 9, U, 16 and 18. . Preferably, the antibody is characterized in that the human heavy chain variable region comprises an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 17, 19 and 20. The CDR regions of the heavy and light chains are shown in SEQ ID NOS: 21-38 and 39-57. Preferably, the antibody is characterized in that the antibody comprises a light chain variable domain as defined by the amino acid sequence SEQ ID ΝΟ:1 and a heavy chain variable domain defined by SEQ ID NO: 2, 17 or 20. Preferably, the antibody is characterized in that the human heavy chain constant region comprises an amino acid sequence independently selected from the group consisting of the heavy chain constant regions of SEQ ID NO: 14 and 15 or SEQ ID NO: 58. Preferably, the antibody is characterized in that the antibody comprises the kappa light chain constant region of SEQ ID NO: 13 or the light chain constant region of SEQ ID NO: 61, 65 or 69. Preferably, an antibody of the invention is characterized by binding to OX40L and belonging to the human IgGl class (wild type) and comprising the gamma heavy chain SEQ ID NO: 58, 62 or 66. Particularly preferred are antibodies comprising: a) y heavy chain SEQ ID NO: 58 and kappa light chain SEQ ID NO: 61, b) Y heavy chain SEQ ID NO: 62 and kappa light chain SEQ ID NO: 65, or . 7 heavy chain 8 ugly (^10 1^0: 66 and 1 <: light chain 8 ugly (^10 1^0: 69. Another embodiment of the invention is a formulation comprising an antibody that binds to OX40L, It is characterized in that it is composed of cell lines hu-Mab<hOX40L> LC.001, hu-Mab <hOX40L> LC.005, hu-Mab<hOX40L> LC.010, hu-Mab <hOX40L> LC.019, hu- Mab<hOX40L> LC.029 or hu-Mab <hOX40L> LC.033 is produced as described in WO 2006/029879. 140095.doc 201000128 The antibody is preferably a chimeric human or humanized antibody. Preferably, the KD value associated with OX40L in the BIAcore analysis is less than 1 (Τ8 M (10·12 to 1 (Γ8 M), and the better KD is in the range of 1〇_12 to 1〇_9 Μ Inside.

較佳地，該抗體在使用塗佈濃度為0.5 pg/ml之固定 OX40L(較佳係固定在鏈黴抗生物素表面上之生物素化 OX40L)的ELISA分析中可抑制OX40L與0X40間之相互作 用，其中IC50值至多為4 nM。更佳地，IC50值係在1-4 nM 範圍内。 該抗體之特徵較佳在於該抗體不與補體因子Clq結合， 此係指在ELISA分析量測中以10 pg/ml之濃度的該抗體對 Clq之最大結合（Bmax)與抗體LC.001之Bmax相比係其之 30%或更低，較佳係20%或更低。 較佳地，抗體不會結合至人類FcyRI、FcyRIIA及/或 FcyRIIIA。尤佳地，該抗體不會結合至NK效應細胞上之人 類Fey受體。 該抗體之特徵較佳在於該抗體不與NK細胞上之Fey受體 結合，此係指在分析中以20 pg/ml之濃度的該抗體對NK細 胞之最大結合（Bmax)為抗體LC.001之Bmax的20%或更低， 較佳係10%或更低。 抗體之特徵較佳在於其不會結合至FcyRI。此意指該抗 體之特徵在於，當在測試該抗體以0.078-10 pg/ml範圍内 之濃度對缺乏FcyRIIA及FcyllB但可表現重組FcyRI之B-細 胞淋巴瘤細胞之結合的分析中量測時，該抗體之EC50值係 140095.doc 201000128 LC.001之EC50值的5倍或更多，較佳係7倍或更多，例如8 倍或更多。 該抗體之特徵較佳在於其係包含至少一處胺基酸突變 (較佳位於人類Fc部分）之IgG4抗體或IgGl抗體，該突變可 使其不會結合至補體因子Clq及/或不會結合至NK細胞上 之人類Fογ受體。 該抗體之特徵較佳在於其不會活化補體因子C3。 該抗體之特徵較佳在於屬於人類亞類IgG4。在本發明之 又一較佳實施例中，調配物包含特徵在於以下之抗體：屬 於任一 IgG類別，較佳係IgGl或IgG4，在E233、L234、 L235 、 G236 、 D270 、 N297 、 E318 、 K320 、 K322 、 A327、A330、P331及/或P329(根據EU索引編號）中含有至 少一個突變。尤佳者係IgGl突變PVA236、L234A/ L235A 及/或GLPSS331、以及IgG4突變L23 5E。更佳該IgG4亞類 抗體含有突變S228P或突變S228P及L235E(Angal等人， Mol. Immunol. 30(1993)105-108)。 因此，該抗體較佳係人類亞類IgGl抗體，含有一或多個 來自 PVA236、GLPSS331 及/或 L234A/L235A之突變（根據 EU索引編號）。 較佳地，該抗體之特徵在於結合至OX40L、屬於含有突 變L234A/L235A之IgGl類別，且包含γ重鏈SEQ ID NO: 59 ' 63或67 ° 尤佳者係包含以下之抗體： &)丫重鏈8丑(^1〇>10:59及代輕鏈8丑(5 1〇]^〇:61’ 140095.doc 201000128 b)γ重鏈SEQIDNO:63及κ輕鏈SEQIDNO:65，或 。）7重鏈8丑〇10^^0:67及〖輕鏈8£()10>10:69。 較佳地，抗體之特徵在於屬於含有突變S228P之IgG4類 別、包含γ重鏈SEQ ID NO: 60、64或68。 尤佳者係包含以下之抗體： a) γ重鏈 SEQ ID NO:60及 κ輕鏈 SEQ ID NO:61， b) y 重鏈 SEQ ID NO:64 及 κ 輕鏈 SEQ ID NO:65，或 c) γ重鏈SEQIDNO:68及κ輕鏈SEQIDNO:69。 本發明抗體之特徵較佳在於不會引發補體依賴性細胞毒 性（CDC)。 該抗體之特徵較佳在於不會引發抗體依賴性細胞毒性 (ADCC)。 因此，本發明之調配物包含抗OX40L抗體或單一重鏈或 輕鏈，其特徵在於CDRs、可變區、全胺基酸序列或雜交 瘤，且不包含Fc部分或包含任一類型的Fc部分，較佳人類 IgGl Fc或人類IgG4 Fc，來自人類來源未經修飾或由上述 突變修飾。 因此，本發明之調配物亦包含特徵在於以下之抗體（較 佳為單株抗體）：該等抗體可結合OX40L、含有來自人類 來源之Fc部分且不會結合人類補體因子Clq及/或NK細胞 上之人類FcY受體、屬於人類IgG4型或二者均經上述突變 修飾之人類IgG 1或人類IgG4。 因此，本發明調配物亦包含特徵在於以下之抗體（較佳 為單株抗體）·該等單體可以100 ng之抗體濃度結合至 140095.doc -10- 201000128 OX40L及變性〇X40L(以西方墨點法）。該等抗體可結合至 與單株抗體LC.001結合之抗原決定部位相同的〇x4〇l多肽 抗原決疋部位上。s亥等抗體不包含心部分或包含野生型或 經上述突變修飾之任一類型的以部分（較佳為人類1§〇或 人類IgG4)。 在個實施例中，本發明提供一種其中抗體係以1 〇_丨5〇 mg/mL、較佳i〇_5〇 mg/mL範圍之量存在的調配物。 可藉由重組方式（例如，藉由彼等闞述於WO 2006/029879 中者）製造抗OX40L之單株拮抗抗體。該等方法在此項技 術湏域中廣泛热知且包含於原核及真核細胞中表現蛋白質 以及隨後分離抗體多肽且通常將其純化至醫藥上可接受之 & JL it 4T蛋白質表現時’藉由標準方法將編碼輕鍵及重 键之核酸或其片段插入至表現載體中。表現係在適當原核 或真核宿主細胞（例如⑽細胞、刪細胞、sp細細胞、 騰293細胞:⑽細胞、酵母細胞或大腸埃希桿菌細胞） ❹:實施且藉由標準技術（例如，包括驗/SDS處理、CsC1 帶法B柱層析法、瓊脂醣凝膠電泳及其他已為業 内所熟知者）自細胞（溶胞後之上清液或細胞）回收抗體，如 WO 2006/029879 中所述。 本^所用術5吾「緩衝劑」表示可穩定醫藥製劑之pH的醫 f上可接受之賦形劑。適宜緩衝劑已為業内所熟知且可參 =獻較佳醫樂上可接受之緩衝劑包含（但不限於）組胺 酸緩衝劑、摔樣酸趨镑 衝劑、琥珀酸鹽緩衝劑、乙酸鹽緩 衝劑、鱗酸鹽緩衝劑、籍 ㈣積^酸緩衝劑或其混合物。仍較佳 140095.doc 201000128 緩衝劑包含利用業内熟知之酸或鹼進行pH調節之L-組胺酸 或L-組胺酸與L-組胺酸鹽酸鹽的混合物。上述緩衝劑通常 係以約1 mM至約1〇〇 mM、較佳約5 mM至約5〇 mM其更佳 約10-20 mM之量使用。獨立於所用緩衝劑，可用業内熟知 之酸或鹼（例如，鹽酸、乙酸、磷酸、硫酸及檸檬酸、氫 氧化鈉及氫氧化鉀）將pH調節至包含約4.0至約7.0且較佳約 5 · 0至約6.5且仍較佳約5.5至約6.5之值下。 本文所用術語「表面活性劑」表示用於保護蛋白調配物 抵抗機械應力（例如攪拌及剪切）的醫藥上可接受之賦形 劑。醫藥上可接受之表面活性劑的實例包括聚氧乙烯失水 山梨酵脂肪酸酯（Tween)、聚氧乙烯烷基醚（Brij)、烷基苯 基聚氧乙烯醚（Triton-X)、聚氧乙烯-聚氧丙烯共聚物（泊洛 沙姆（Poloxamer)、普流尼克（Pluronic))、及十二烷基硫酸 鈉（SDS)。較佳聚氧乙烯失水山梨醇_脂肪酸酯係聚山梨醇 酯20(以商標Tween 2〇tm出售）及聚山梨醇酯80(以商標 Tween 8〇τμ出售）。較佳聚乙烯-聚丙烯共聚物係彼等以商 品名Pluronic® F68或Poloxamer 188ΤΜ出售者。較佳聚氧乙 烯烷基醚係彼等以商標Brij™出售者。較佳烷基酚聚氧乙 烯醚係以商品名Triton-X出售者。當使用聚山梨醇酯2〇 (Tween 2〇tm)及聚山梨醇酯8〇 (Tween 8〇TM)時，其通常係 以約0.001-約1%、較佳約0.005-約0.2%且更佳約〇 〇1_約 0.1% w/v(重量/體積）之濃度範圍使用。 術語「穩定劑」表示可保護活性醫藥成份及/或調配物 在製造、儲存及應用期間免於化學及/或物理降解之醫藥 140095.doc -12- 201000128 上可接受的賦形劑。蛋白醫藥品之化學及物理降解途徑係 由 Cleland等人，（1993)，Crit Rev Ther Drug Carrier Syst 10(4):307-77, Wang (1999) Int J Pharm 185(2):129-88, Wang (2000) Int J Pharm 203(1-2):1-60及 Chi 等人（2003) Pharm Res 20(9):1325-36檢查。穩定劑包括（但不限於）如 下文所定義之糖、胺基酸、多元醇、環糊精（例如，羥丙 基-β-環糊精、磺丁基乙基-β-環糊精、β-環糊精）、聚乙二 醇（例如，PEG 3000、PEG 3350、PEG 4000、PEG 6000)、 ® 白蛋白、人類血清白蛋白（USA)、牛血清白蛋白（BSA)、鹽 (例如’氯化鈉、氯化鎂、氣化鈣）、螯合劑（例如， EDTA)。如上文中所述’穩定劑可以約ίο-約500 mM之 量、較佳以約10約3 00 mM之量且更佳以約丨〇〇 mM-約3 00 mM之量存在於調配物中。 本文所用術語「糖」表示單糖或寡糖。單糖係不可由酸 水解之單體碳水化合物，其包括簡單糖及其衍生物，例如 0 胺基糖。單糖之實例包括葡萄糖、果糖、半乳糖、甘露 糖、山梨糖、核糖、脫氧核糖、神經胺糖酸。寡糖係由一 種以上單體糖單元經由一或多個糖苷鍵連接而組成之碳水 化合物’其可具支鏈或呈單鏈狀。募糖内之單體糖單元可 相同或不同。根據單體糠單元之數量，募糖可係二糖、三 糖、四糖、五糖等等。與多糖相反，單糖及寡糖具有水溶 性。寡糖之實例包括蔗糠、海藻糖、乳糖、麥芽糖及棉子 糖。較佳糖係蔗糖及海藻糖、最佳者係海藻糖。 本文所用術語「胺基酸」表示具有位於羧酸基團之〇1位 140095.doc •13· 201000128 置處之胺基部分的醫藥上可接受之有機分子。胺基酸之實 例包括精胺酸、甘胺酸、烏胺酸、離胺酸、組胺酸、麩胺 酸、天冬胺酸、異白胺酸、白胺酸、丙胺酸、苯丙胺酸、 酪胺酸、色胺酸、甲硫胺酸、絲胺酸、脯胺酸。胺基酸通 常係以約10-500 mM之量、較佳以約1〇_約3〇〇 之量且 更佳以約1 〇〇·約3〇〇 mM之量使用。 本文所用術S吾「多元醇」表示具有一個以上羥基之醫藥 上可接焚之醇。適宜多元醇包含（但不限於）甘露醇、山梨 醇、甘油、葡聚糖、丙三醇、阿拉伯糖醇、丙二醇、聚乙 二醇及其組合。多元醇可以約10 mM約500 mM之量較 佳以約10-約300 rnM之量且更佳以約1〇〇_約3〇〇 mM之量使 用0 穩定劑内之子群係康乾保護劑。術語「;東乾冷;東劑」表 示可在來乾過程、後續儲存及重構期間保護不穩定活性成 份（例如’蛋白質）免受去敎條件之醫藥上可接受的賦形 劑。床乾保護劑包含（但不限於）由糖、多㈣（例如，糖 醇）及胺基酸組成之群。較佳凍乾保護劑可選自由以下組 成之群：糖（例如，嚴糖、海藻糖、乳糖、葡萄糖、甘露 糖、麥芽糖、半乳糖、果糖、山梨糖、棉子糖'神經胺糖 酸、諸如葡萄糖胺、半乳糖胺、N_甲基葡萄糖胺（「葡 胺」）等胺基糖）、多元醇（例如甘露醇及山梨醇）、及胺美 酸（例如精胺酸及甘胺酸）。；東乾保護劑通f係以約1〇_5〇土〇 福之量 '較佳以約Π)-約扇mM之量且更佳以㈣〇約 300 mM之量使用。 140095.doc -14- 201000128 穩疋劑内之子群餘氧化劑。術語「抗氧㈣」表禾可 防止^ 生醫藥成份氧化之醫藥上可接受的賦形劑。抗氧化 劑t 3 (但Γ限於）抗壞灰酸、谷耽甘肽、半胱胺酸、〒硫 胺酸、棒椒酸、EDTA。J乂备矛丨-r DTA抗虱化劑可以約1-約100 mM之 量、較佳以W〇mM之量且更佳以約5_約2〇碰之量 使用。 ❹ ❹ 本文所用術語「張力劑」表示醫藥上可接受之張力劑。 張力制㈣節調配物之渗透性。調配物可具有低渗性、 :滲性或高滲性。-般而言’等滲性係指相對於溶液(通 常相對於人類血清)之滲透慶。本發明之調配物可具有低 渗性、等渗性或高滲性但較佳應具有等渗性。等滲性調配 物係液體或自固體形式（例如，自减乾形式）重構之液體， 並表不具有與和其相比，較之某些其他溶液（例如生理鹽溶 ' ’月）相同，㈣性之溶液。適宜張力劑包含（但不限於） 氣化納、氟切、甘油及來自胺基料之任—組份、糖 (尤其葡萄糖）。張力劑通常係以約5 mM-約500 mM之量使 用0 在穩疋劑及張力劑内有—组可以兩種方式起作用（亦 P其可同時為穩定劑及張力齊J )之化合物。纟實例可參 ^糖胺基酸、多元醇、環糊精、$乙二醇及鹽之群。 '同時作為穩定劑及張力劑之糖的實例係海蕩糖。 八：口物亦可含有佐劑，例如防腐劑、潤濕劑、乳化剤及 政^ ° #由滅菌程序，並藉由引人各種抗細菌劑及抗真 (例如’對羥基苯甲酸、氯丁醇、苯酚、山梨酸及諸 140095.d〇i -15- 201000128 如此類）可確保防止微生物存在。防腐劑通常係以約0 001_ 約2%(w/v)之量使用。防腐劑包含（但不限於）乙醇、苯甲 醇、苯酚、間〒酚、對氣間曱酚、對羥基苯甲酸甲醋或對 經基苯甲酸丙醋、苯紮氣敍（benzalkonium chloride)。 本文中與本發明調配物一起使用之術語「液體」表示在 至少約2-約8°C之溫度下於常壓下為液體之調配物。 本文中與本發明調配物一起使用之術語「凍乾物」表示 藉由本身已為業内所熟知之冷凍-乾燥方法製造之調配 物。藉由冷凍、之後於真空下昇華及於高溫下解吸附殘餘 錄 水而去除溶劑（例如，水）。凍乾物通常具有約〇1_5% (w/w)之殘餘水份且作為粉末或物理穩定之餅存在。柬乾 物之特徵在於在添加重構介質後快速溶解。 本文中與本發明調配物一起使用之術語「重構調配物」 表不藉由添加重構介質凍乾及再溶解之調配物。重構介質 包含（但不限於）注射用水（WFI)、注射用抑菌水（BWFI)、 氣化鈉溶液（例如0·9% (w/v) NaC1)、葡萄糖溶液（例如 匍萄糖）、含表面活性劑之溶液（例如，〇 〇1%聚山梨醇酯 ◎ 2〇)、pH緩衝溶液（例如，磷酸鹽緩衝溶液）。 本發明調配物可用來在哺乳動物、較佳在懷疑具有或患 有發炎疾病之患者中預防及/或治療此一疾病。此等疾病 l括諸如哮„而等過敏反應。其他應用係治療自體免疫性疾 病’包括類風濕性關節炎。 、 較佳地’本發明調配物可用來治療其症狀用吸入腎上腺 皮質類固醇不能充分控制之患者中的嚴重持續性哮喘。患 140095.doc -16- 201000128 者群體包括患有未充分控制之嚴重持續性哮喘之成人及青 >、年（年齡在12歲及更大者）。較佳地每月經皮下遞送調配 物一次或兩次。較佳地，主終點將會在急性惡化中降低。 其他終點包括尖峰呼氣流、日間哮喘症狀、夜醒、生活品 • 貝、急诊室就醫、無哮喘天數、β-2激動劑使用、類固醇 降低或漸減以及對過度反應性之作用。 另外較佳使用本發明調配物單一治療或與胺曱蝶呤或其 ❹ 他DMARDs(緩和疾病之抗風濕藥）組合治療患有中度至重 度活動性類風濕性關節炎之成人。每2週或4週經皮下注射 投與。在一或多種DMARDs無效之患者中為慢性治療。終 點包括患有活動性類風濕性關節炎之成人患者症候及症狀 之減少及結構損傷進行之抑制。由ACR準則測量傷殘之預 防、症候與症狀之改善（ACR20>60%，ACR50>35%， ACR70>15°/〇 ;指標來自美國風濕病學院（American c〇Uege of Rheumatology)，www.rheumat〇i〇gy.c〇m)。 〇 本發明進一步包含使用本發明調配物製造供治療哮喘之 藥劑。 本發明之組合物可藉由此項技術中熟知之多種方法投 與。如熟習此項技術者瞭解，投藥途徑及/或方式應視所 '期望結果而變化。 由某些技與途徑投與本發明組合物，可能需要在稀釋劑 中稀釋組合物。醫藥上可接受之稀釋劑包括鹽水、範萄 糖、林格氏（Ringer)及水緩衝溶液。 本文所用片語「非經腸投與」及「以非經腸方式投與」 140095.doc 201000128 意指除經腸及局部投與以外的投與方式，通常藉由注射， 包括（但不限於）經靜脈内、經肌内、經動脈内、經鞘内、 經囊内、經眼窩内、經心臟内、經皮内、經腹膜内、經氣 管、經皮下、經表皮下、經關節内、經囊下、經蛛網膜 下、經脊柱内、硬膜外及經胸骨内注射及輸注。 該組合物必須滅菌，且係達到該組合物可以注射器遞送 程度之流體。除水外，載劑可為等滲緩衝鹽水溶液、乙 醇、多元醇（例如丙三醇、丙二醇、及液體聚乙二醇、及 諸如此類）及其適宜混合物。 本發明調配物可藉由靜脈内（i.v.)、皮下（s.c.)或諸如醫 藥技術中熟知之任何其他非經腸方式投與。 本發明調配物可藉由業内所熟知之方法（例如，超濾-反 濾、透析、加成及混合、凍乾、重構及其組合）來製備。 製備本發明調配物之實例可參見下文。 【實施方式】 實例 實例1 :液體調配物之製備 藉由均化huMAb OX40L存於生產緩衝劑（例如，於約pH 6.0下含有240 mM海藻糖及0.02% (w/v)聚山梨醇酯20之20 mM組胺酸緩衝劑、或於pH 5.5下含有240 mM蔗糖、20 mM精胺酸及0.02% (w/v)聚山梨醇酯20之20 mM檸檬酸鹽 缓衝劑）之溶液製備濃度為約20 mg/mL的huMAb OX40L調 配物。 所有調配物經0.22 μηι低蛋白結合濾膜無菌過滤並在氮 140095.doc -18- 201000128 氣氛圍下以無菌方式填充至用塗覆ETFE(乙烯與四氟乙稀 之共聚物）之橡膠塞及紹榧夹帽封閉之無菌6 mL玻璃小瓶 内。填充體積為約2.4 mL。於不同氣候條件（5〇c、25〇c及 4 0 C )下儲存s玄等調配物不同時間間隔且藉由振盡（分別在 5°C或25°C下以200 min·1之振盪頻率振盪一周）及冷束_解象 應力法施加應力。在施加應力測試之前及之後藉由丨）uv 分光光度法及2)尺寸排除層析法（SEC)分析樣品。 使用尺寸排除層析法（SEC)檢測調配物中之可溶性高分 子量物質（團聚體）及低分子量水解產物（LMW)。在配備有 TSKgel G3000 SWXL 管柱（7.8x300 mm)之 Water Alliance 2795 HPLC儀器上實施分析。藉由等度洗脫曲線使用pH 7.0之0.2 M K2HPO4/0.25M KCL作為流動相分離完整單 體、團聚體及水解產物且在280 nm波長下對其進行檢測。 在240 nm至400 nm波長範圍内之Varian Cary Bio UV分光 光度計上實施用於測定蛋白含量之UV光譜法。將淨蛋白 樣品用相應調配物緩衝劑稀釋至約0.5 mg/mL。根據等式1 計算蛋白濃度。 等式1 蛋白含量 卓280)-2(320) X稀釋因子 將280 nm下之UV光吸收校正為320 nm下之光散射且乘 以稀釋因子，該稀釋因子係由純淨樣品及稀釋緩衝劑之稱 量質量及密度確定。分子除以產物之比色孤路徑長度d及 消光係數ε。 140095.doc -19· 201000128 表1 : 調配物A 儲存於2-8°C下 於pH 6.0下， 20 mg/mL MAb OX40L ' 20 mM L-組胺酸HQ、 240 mM海藻糖、 0.02%聚山梨醇酯20 時間點 蛋白濃度 (mg/mL) 尺寸排除-HPLC HMW(%)單體(％) LMW (%) 初始 18.7 1.4 97.8 0.8 1個月 18.1 1.4 97.9 0.7 2個月 18.7 1.3 98.0 0.7 3個月 19.1 1.4 97.8 0.8 調配物A 儲存於40°C下 於pH 6.0下， 20 mg/mL MAb OX40L ' 20 mM L-組胺酸 HC1、 240 mM海藻糖、 0.02%聚山梨醇酯2〇 時間點 蛋白濃度 (mg/mL) 尺寸排除-HPLC HMW (%)單體(％) LMW (%) 初始 18.7 1.4 97.8 0.8 1個月 18.4 0.8 98.0 1.1 2個月 18.4 0.7 96.0 3.1 3個月 19.1 0.8 92.4 6.7 調配物B 儲存於2-8°C下 於pH 5.5下， 20 mg/mL MAb OX40L、 20 mM檸檬酸鹽緩衝劑、 240mM蔗糖 20mM精胺酸 0.02%聚山梨醇醋20 140095.doc •20- 201000128 時間點 蛋白濃度 (mg/mL) 尺寸排除-HPLC HMW(°/。）單體(％) LMW (%) 初始 20.7 1.6 97.6 0.8 1個月 19.9 1.5 97.7 0.8 2個月 20.5 1.4 97.8 0.7 調配物B 儲存於40°C下 於pH 5.5下， 20 mg/mL MAb OX40L ' 20 mM檸檬酸鹽緩衝劑、 240 mM蔗糖 20 mM精胺酸 0.02%聚山梨醇酯20 時間點 蛋白濃度 (mg/mL) 尺寸排除-HPLC HMW (%)單體(％) LMW (%) 初始 20.7 1.6 97.6 0.8 1個月 19.4 0.7 92.7 6.6 2個月 20.4 0.7 87.6 11.7 實例2:凍乾調配物及自凍乾調配物重構之液體調配物的 製備 如實例1中所述製備約20 mg/ml MAB 0X40之溶液並使 用表2中所報告之冷凍-乾燥循環進行凍乾。Preferably, the antibody inhibits the interaction between OX40L and 0X40 in an ELISA assay using a fixed concentration of OX40L (preferably biotinylated OX40L immobilized on a streptavidin surface) at a coating concentration of 0.5 pg/ml. Function, where the IC50 value is at most 4 nM. More preferably, the IC50 value is in the range of 1-4 nM. Preferably, the antibody is characterized in that the antibody does not bind to complement factor Clq, which refers to the maximum binding of the antibody to Clq (Bmax) and the Bmax of antibody LC.001 at a concentration of 10 pg/ml in an ELISA assay. It is preferably 20% or less, more preferably 20% or less. Preferably, the antibody does not bind to human FcyRI, FcyRIIA and/or FcyRIIIA. More preferably, the antibody does not bind to the human Fey receptor on NK effector cells. Preferably, the antibody is characterized in that the antibody does not bind to the Fey receptor on NK cells, which means that the maximum binding (Bmax) of the antibody to NK cells at a concentration of 20 pg/ml in the assay is antibody LC.001. The Bmax is 20% or less, preferably 10% or less. The antibody is preferably characterized in that it does not bind to FcyRI. This means that the antibody is characterized by an assay in the assay for binding of the antibody to a B-cell lymphoma cell lacking FcyRIIA and FcyllB but exhibiting recombinant FcyRI at a concentration ranging from 0.078 to 10 pg/ml. The EC50 value of the antibody is 5 times or more, preferably 7 times or more, for example 8 times or more, of the EC50 value of 140095.doc 201000128 LC.001. Preferably, the antibody is characterized in that it comprises at least one IgG4 antibody or IgG1 antibody having an amino acid mutation (preferably located in the human Fc portion) which allows it to not bind to the complement factor Clq and/or does not bind. Human Fογ receptor on NK cells. The antibody is preferably characterized in that it does not activate complement factor C3. The antibody is preferably characterized by belonging to the human subclass IgG4. In still another preferred embodiment of the present invention, the formulation comprises an antibody characterized by being of any IgG class, preferably IgGl or IgG4, at E233, L234, L235, G236, D270, N297, E318, K320 , K322, A327, A330, P331 and/or P329 (according to the EU index number) contain at least one mutation. Particularly preferred are the IgG1 mutations PVA236, L234A/L235A and/or GLPSS331, and the IgG4 mutation L23 5E. More preferably, the IgG4 subclass antibody comprises the mutation S228P or the mutations S228P and L235E (Angal et al, Mol. Immunol. 30 (1993) 105-108). Thus, the antibody is preferably a human subclass IgGl antibody containing one or more mutations from PVA236, GLPSS331 and/or L234A/L235A (according to the EU index numbering). Preferably, the antibody is characterized by binding to OX40L, belonging to the IgGl class containing the mutation L234A/L235A, and comprising the gamma heavy chain SEQ ID NO: 59 '63 or 67 °. The preferred antibody comprises the following antibodies: &)丫 heavy chain 8 ugly (^1〇>10:59 and generation light chain 8 ugly (5 1〇]^〇: 61' 140095.doc 201000128 b) γ heavy chain SEQ ID NO: 63 and κ light chain SEQ ID NO: 65, Or.) 7 heavy chain 8 ugly 10 ^ ^ 0: 67 and 〖 light chain 8 £ () 10 > 10: 69. Preferably, the antibody is characterized by belonging to the IgG4 class comprising the mutated S228P, comprising the gamma heavy chain SEQ ID NO: 60, 64 or 68. Particularly preferred are antibodies comprising: a) gamma heavy chain SEQ ID NO: 60 and kappa light chain SEQ ID NO: 61, b) y heavy chain SEQ ID NO: 64 and kappa light chain SEQ ID NO: 65, or c) gamma heavy chain SEQ ID NO: 68 and kappa light chain SEQ ID NO: 69. The antibodies of the invention are preferably characterized by not causing complement dependent cytotoxicity (CDC). The antibody is preferably characterized by not eliciting antibody-dependent cellular cytotoxicity (ADCC). Thus, a formulation of the invention comprises an anti-OX40L antibody or a single heavy or light chain, characterized by CDRs, variable regions, peramino acid sequences or hybridomas, and does not comprise or comprise any type of Fc portion Preferably, human IgG1 Fc or human IgG4 Fc is unmodified from human sources or modified by the above mutations. Thus, the formulations of the invention also comprise antibodies (preferably monoclonal antibodies) which are characterized by binding to OX40L, containing an Fc portion from a human source and not binding to human complement factor Clq and/or NK cells The human FcY receptor, human IgG4 or both of which are modified by the above mutations. Accordingly, the formulations of the present invention also comprise antibodies (preferably monoclonal antibodies) characterized by the combination of these monomers at a concentration of 100 ng to 140095.doc -10- 201000128 OX40L and denatured x40L (in western ink) Point method). These antibodies bind to the same 〇x4〇l polypeptide epitope as the epitope to which the monoclonal antibody LC.001 binds. The antibody such as shai does not contain a cardiac moiety or a part containing any of the wild type or modified by the above mutation (preferably human 1 § or human IgG 4). In one embodiment, the invention provides a formulation wherein the anti-system is present in an amount ranging from 1 〇 丨 5 〇 mg/mL, preferably i 〇 5 〇 mg/mL. Individual antagonist antibodies against OX40L can be made by recombinant means (e.g., as described in WO 2006/029879). Such methods are widely known in the art and are included in prokaryotic and eukaryotic cells to express proteins and subsequently isolate antibody polypeptides and are typically purified to pharmaceutically acceptable & JL it 4T protein expressions. The nucleic acid encoding the light and heavy bonds or a fragment thereof is inserted into the expression vector by standard methods. Expressed in a suitable prokaryotic or eukaryotic host cell (eg, (10) cells, cells, sp cells, 293 cells: (10) cells, yeast cells, or Escherichia coli cells): implemented and by standard techniques (eg, including Recovery/SDS treatment, CsC1 band B-column chromatography, agarose gel electrophoresis, and others well known in the art) recover cells from cells (clear or cells after lysis), as in WO 2006/029879 Said in the middle. The "buffering agent" used in the present invention means an acceptable excipient which stabilizes the pH of the pharmaceutical preparation. Suitable buffers are well known in the art and can be used as a preferred medically acceptable buffer comprising, but not limited to, a histidine buffer, a succinic acid buffer, a succinate buffer, Acetate buffer, sulphate buffer, (iv) acid buffer or a mixture thereof. Still preferred 140095.doc 201000128 The buffer comprises a mixture of L-histamine or L-histamine and L-histamine hydrochloride, pH adjusted using acids or bases well known in the art. The above buffering agent is usually used in an amount of from about 1 mM to about 1 mM, preferably from about 5 mM to about 5 mM, more preferably from about 10 to 20 mM. Independent of the buffer employed, the pH can be adjusted to comprise from about 4.0 to about 7.0 and preferably from an acid or base well known in the art (e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, and citric acid, sodium hydroxide, and potassium hydroxide). 5 · 0 to about 6.5 and still preferably at a value of about 5.5 to about 6.5. The term "surfactant" as used herein denotes a pharmaceutically acceptable excipient for protecting a protein formulation against mechanical stresses such as agitation and shear. Examples of pharmaceutically acceptable surfactants include polyoxyethylene dehydrated sorbitan ester esters (Tween), polyoxyethylene alkyl ethers (Brij), alkyl phenyl polyoxyethylene ethers (Triton-X), poly Oxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic), and sodium dodecyl sulfate (SDS). Preferred are polyoxyethylene sorbitan _ fatty acid ester polysorbate 20 (sold under the trademark Tween 2〇tm) and polysorbate 80 (sold under the trademark Tween 8〇τμ). Preferred polyethylene-polypropylene copolymers are sold under the tradename Pluronic® F68 or Poloxamer 188®. Preferred polyoxyethylene alkyl ethers are sold under the trademark BrijTM. Preferred alkyl phenol ethoxylates are sold under the trade name Triton-X. When polysorbate 2 (Tween 2〇tm) and polysorbate 8 (Tween 8®TM) are used, it is usually from about 0.001 to about 1%, preferably from about 0.005 to about 0.2%, and more A concentration range of about 0.1% w/v (weight/volume) is used. The term "stabilizer" means a drug that protects active pharmaceutical ingredients and/or formulations from chemical and/or physical degradation during manufacture, storage, and application. 140095.doc -12- 201000128 Acceptable excipients. The chemical and physical degradation pathways of protein pharmaceuticals are by Cleland et al. (1993), Crit Rev Ther Drug Carrier Syst 10(4): 307-77, Wang (1999) Int J Pharm 185(2): 129-88, Wang (2000) Int J Pharm 203 (1-2): 1-60 and Chi et al. (2003) Pharm Res 20(9): 1325-36. Stabilizers include, but are not limited to, sugars, amino acids, polyols, cyclodextrins as defined below (eg, hydroxypropyl-β-cyclodextrin, sulfobutylethyl-β-cyclodextrin, Β-cyclodextrin), polyethylene glycol (eg, PEG 3000, PEG 3350, PEG 4000, PEG 6000), ® albumin, human serum albumin (USA), bovine serum albumin (BSA), salt (eg 'Sodium chloride, magnesium chloride, calcium carbonate), chelating agent (eg, EDTA). The stabilizer may be present in the formulation in an amount of from about 5,000 mM, preferably from about 10 to about 300 mM, and more preferably from about mM mM to about 30,000 mM, as described above. The term "sugar" as used herein denotes a monosaccharide or oligosaccharide. Monosaccharides are monomeric carbohydrates which are not hydrolyzable by acid, and include simple sugars and derivatives thereof, such as 0 amino sugars. Examples of the monosaccharide include glucose, fructose, galactose, mannose, sorbose, ribose, deoxyribose, and ceramide. An oligosaccharide is a carbohydrate composed of more than one monomeric sugar unit linked via one or more glycosidic linkages. It may be branched or monochained. The monomeric sugar units in the sugar collection may be the same or different. According to the number of monomer units, the sugar can be disaccharide, trisaccharide, tetrasaccharide, pentasaccharide or the like. In contrast to polysaccharides, monosaccharides and oligosaccharides are water soluble. Examples of the oligosaccharide include sugarcane, trehalose, lactose, maltose, and raffinose. Preferred sugars are sucrose and trehalose, and the best is trehalose. The term "amino acid" as used herein denotes a pharmaceutically acceptable organic molecule having an amine moiety at the position of the carboxylic acid group at position 140095.doc •13·201000128. Examples of amino acids include arginine, glycine, uric acid, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, Tyrosine, tryptophan, methionine, serine, valine. The amino acid is usually used in an amount of about 10 to 500 mM, preferably about 1 Torr to about 3 Torr, and more preferably about 1 Torr to about 3 mM. As used herein, "polyol" means a pharmaceutically acceptable alcohol which has more than one hydroxyl group. Suitable polyols include, but are not limited to, mannitol, sorbitol, glycerin, dextran, glycerol, arabitol, propylene glycol, polyethylene glycol, and combinations thereof. The polyol may be used in an amount of about 10 mM, about 500 mM, preferably in an amount of about 10 to about 300 rnM, and more preferably in an amount of about 1 Torr to about 3 mM. . The term "Donggan Leng; East Agent" means a pharmaceutically acceptable excipient that protects an unstable active ingredient (e.g., 'protein) from de-sputing conditions during the dry process, subsequent storage, and reconstitution. Bed dry protectants include, but are not limited to, a group consisting of sugars, poly(tetra) (e.g., sugar alcohols), and amino acids. Preferably, the lyoprotectant is selected from the group consisting of sugars (eg, sugar, trehalose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, raffinose, neuraminic acid, Amino sugars such as glucosamine, galactosamine, N-methylglucamine ("glucamine"), polyols (such as mannitol and sorbitol), and amine acids (such as arginine and glycine) ). The Donggan protectant is used in an amount of about 1 〇 5 〇 〇 之 ' ' 较佳 较佳 较佳 较佳 较佳 较佳 较佳 - - - 约 约 约 约 约 约 约 约 约 约 mM mM mM mM mM mM mM mM mM mM mM mM mM mM mM mM 140095.doc -14- 201000128 The residual oxidant in the group of stabilizers. The term "anti-oxygen (4)" is a pharmaceutically acceptable excipient that prevents oxidation of pharmaceutical ingredients. The antioxidant t 3 (but not limited to) is ascorbic acid, glutathione, cysteine, guanine, baritic acid, EDTA. The J-spray-r DTA anti-deuteration agent can be used in an amount of from about 1 to about 100 mM, preferably in an amount of W mM and more preferably in an amount of from about 5 to about 2 Torr. ❹ ❹ The term "toner agent" as used herein means a pharmaceutically acceptable tonicity agent. The permeability of the tension system (4) is adjusted. Formulations may have hypotonicity, permeability, or hypertonicity. In general, 'isotonicity' refers to the penetration of a solution (usually relative to human serum). The formulations of the present invention may have hypotonicity, isotonicity or hypertonicity but preferably should be isotonic. An isotonic formulation is a liquid or a liquid that has been reconstituted from a solid form (eg, from a reduced dry form) and is shown to be the same as compared to some other solutions (eg, physiological saline 'months') , (d) the solution of sex. Suitable tonicity agents include, but are not limited to, gasified sodium, fluorocut, glycerin, and any components from the amine base, sugars (especially glucose). The tonicity agent is usually used in an amount of from about 5 mM to about 500 mM. The stabilizer is used in a stabilizer and a tonicity agent to form a compound which can act in two ways (also as a stabilizer and a tension at the same time). Examples of hydrazine can be found in the group of glycosamino acids, polyols, cyclodextrins, ethylene glycol and salts. 'An example of a sugar that acts as both a stabilizer and a tonicity agent is a sugar. Eight: The mouth can also contain adjuvants, such as preservatives, wetting agents, emulsified enamels and sterilized procedures, and by introducing various antibacterial agents and anti-sense (such as 'p-hydroxybenzoic acid, chloroprene Alcohols, phenols, sorbic acid and the likes 140095.d〇i -15- 201000128 as such) ensure the prevention of the presence of microorganisms. Preservatives are typically used in amounts of about 0 001 Å to about 2% (w/v). Preservatives include, but are not limited to, ethanol, benzyl alcohol, phenol, m-nonylphenol, p-mentalin, m-hydroxybenzoic acid or p-propyl benzoate, benzalkonium chloride. The term "liquid" as used herein in connection with a formulation of the invention means a formulation which is liquid at atmospheric pressure at a temperature of at least about 2 to about 8 °C. The term "lyophilizate" as used herein in connection with a formulation of the invention means a formulation made by a freeze-drying process which is well known in the art. The solvent (e.g., water) is removed by freezing, sublimation under vacuum, and desorption of residual water at elevated temperatures. The lyophilizate typically has a residual moisture of about 1% to about 5% (w/w) and is present as a powder or a physically stable cake. The Cambodian dry matter is characterized by rapid dissolution after the addition of the reconstituted medium. The term "reconstituted formulation" as used herein in connection with a formulation of the invention is not indicated by the addition of a reconstitution medium to lyophilize and redissolve the formulation. Reconstitution medium includes, but is not limited to, water for injection (WFI), bacteriostatic water for injection (BWFI), sodium vaporized solution (eg, 0.9% (w/v) NaC1), glucose solution (eg, glucosamine) A surfactant-containing solution (for example, 〇〇1% polysorbate ◎ 2 〇), a pH buffer solution (for example, a phosphate buffer solution). The formulations of the invention may be used to prevent and/or treat such a disease in a mammal, preferably in a patient suspected of having or suffering from an inflammatory disease. Such diseases include allergic reactions such as sputum. Other applications are treatment of autoimmune diseases including rheumatoid arthritis. Preferably, the formulation of the present invention can be used to treat symptoms thereof by inhaled corticosteroids. Severe persistent asthma in well-controlled patients. Patients with 140095.doc -16- 201000128 include adults and young adults with under-controlled severe persistent asthma, and years (age 12 and older) Preferably, the formulation is delivered subcutaneously once or twice a month. Preferably, the primary endpoint will be reduced in acute exacerbations. Other endpoints include peak expiratory flow, daytime asthma symptoms, night awakening, lifestyle products, shellfish, emergency department Room for medical treatment, days without asthma, use of beta-2 agonists, reduction or gradual reduction of steroids, and effects on hyperreactivity. It is also preferred to use a single treatment of the formulation of the present invention or with carbendazim or its sputum DMARDs (mitigation disease) An anti-rheumatic drug combination for the treatment of adults with moderate to severe active rheumatoid arthritis. Subcutaneous injection every 2 or 4 weeks. One or more DMARDs Chronic treatment in patients with efficacy. End points include reduction of symptoms and symptoms of adult patients with active rheumatoid arthritis and inhibition of structural damage. Measurement of prevention, symptoms and symptoms of disability by ACR criteria (ACR20> 60%, ACR50 > 35%, ACR70 > 15 ° / 〇; index from the American College of Rheumatology (American c〇 Uege of Rheumatology), www.rheumat〇i〇gy.c〇m) 〇 The present invention further includes the use The formulations of the present invention produce an agent for the treatment of asthma. The compositions of the present invention can be administered by a variety of methods well known in the art. As will be appreciated by those skilled in the art, the route and/or manner of administration should be based on the desired result. While varying the composition of the present invention by some techniques and routes, it may be desirable to dilute the composition in a diluent. Pharmaceutically acceptable diluents include saline, fructose, Ringer, and water buffer solutions. The phrase used in this article is “parenteral administration” and “parenteral administration” 140095.doc 201000128 means a method of administration other than enteral and local administration, usually by injection, (but not limited to) intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous Intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions. The composition must be sterilized and a fluid to the extent that the composition can be delivered by a syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Formulations of the invention may be administered by intravenous (i.v.), subcutaneous (s.c.) or any other parenteral means such as is well known in the art of pharmacy. The formulations of the present invention can be prepared by methods well known in the art (e.g., ultrafiltration-refiltration, dialysis, addition and mixing, lyophilization, reconstitution, and combinations thereof). Examples of the preparation of the formulations of the invention can be found below. EXAMPLES Example 1 : Preparation of a liquid formulation by homogenizing huMAb OX40L in a production buffer (for example, containing 240 mM trehalose and 0.02% (w/v) polysorbate 20 at about pH 6.0 Preparation of 20 mM histidine buffer, or solution containing 240 mM sucrose, 20 mM arginine and 0.02% (w/v) polysorbate 20 in 20 mM citrate buffer at pH 5.5) A huMAb OX40L formulation at a concentration of about 20 mg/mL. All formulations were aseptically filtered through a 0.22 μηι low protein binding filter and aseptically filled in a nitrogen atmosphere of 140095.doc -18-201000128 to a rubber stopper coated with ETFE (copolymer of ethylene and tetrafluoroethylene). The sterile 6 mL glass vial enclosed by the sputum cap is closed. The fill volume is approximately 2.4 mL. Stored in different climatic conditions (5〇c, 25〇c, and 40 C) at different time intervals and by vibration (oscillation at 200 °·1 at 5 °C or 25 °C, respectively) The frequency is oscillated for one week) and the cold beam _ resolution stress method applies stress. Samples were analyzed by 丨)uv spectrophotometry and 2) size exclusion chromatography (SEC) before and after stress testing. The soluble high molecular weight species (agglomerates) and low molecular weight hydrolysates (LMW) in the formulation were examined using size exclusion chromatography (SEC). The analysis was performed on a Water Alliance 2795 HPLC instrument equipped with a TSKgel G3000 SWXL column (7.8 x 300 mm). 0.2 M K2HPO4/0.25M KCL, pH 7.0, was used as the mobile phase to separate intact monomers, agglomerates and hydrolysates by isocratic elution and detected at 280 nm. UV spectroscopy for determining protein content was performed on a Varian Cary Bio UV spectrophotometer in the wavelength range from 240 nm to 400 nm. The net protein sample was diluted to approximately 0.5 mg/mL with the corresponding formulation buffer. The protein concentration was calculated according to Equation 1. Equation 1 Protein content 280)-2 (320) The X dilution factor corrects the UV light absorption at 280 nm to light scattering at 320 nm and multiplies by the dilution factor, which is from a pure sample and a dilution buffer. Weighing quality and density are determined. The molecular division is divided by the product color-issociated path length d and the extinction coefficient ε. 140095.doc -19· 201000128 Table 1: Formulation A Stored at 2-8 ° C at pH 6.0, 20 mg/mL MAb OX40L ' 20 mM L-Histidine HQ, 240 mM Trehalose, 0.02% Poly Sorbitol 20 Time point protein concentration (mg/mL) Size exclusion - HPLC HMW (%) monomer (%) LMW (%) Initial 18.7 1.4 97.8 0.8 1 month 18.1 1.4 97.9 0.7 2 months 18.7 1.3 98.0 0.7 3 Month 19.1 1.4 97.8 0.8 Formulation A Store at 40 ° C at pH 6.0, 20 mg/mL MAb OX40L ' 20 mM L-histidine HC1, 240 mM trehalose, 0.02% polysorbate 2 〇 time Dot protein concentration (mg/mL) Size exclusion - HPLC HMW (%) monomer (%) LMW (%) Initial 18.7 1.4 97.8 0.8 1 month 18.4 0.8 98.0 1.1 2 months 18.4 0.7 96.0 3.1 3 months 19.1 0.8 92.4 6.7 Formulation B Store at 2-8 ° C at pH 5.5, 20 mg/mL MAb OX40L, 20 mM citrate buffer, 240 mM sucrose 20 mM arginine 0.02% polysorbate 20 140095.doc •20 - 201000128 Time point protein concentration (mg/mL) Size exclusion - HPLC HMW (° / .) monomer (%) LMW (%) Initial 20.7 1.6 97.6 0.8 1 month 19.9 1.5 97.7 0.8 2 months 20.5 1.4 97.8 0.7 Formulation B Stored at 40 ° C at pH 5.5, 20 mg/mL MAb OX40L ' 20 mM citrate buffer, 240 mM sucrose 20 mM arginine 0.02% polysorbate 20 time point protein concentration (mg/mL) Size exclusion - HPLC HMW (%) monomer (%) LMW (%) Initial 20.7 1.6 97.6 0.8 1 month 19.4 0.7 92.7 6.6 2 months 20.4 0.7 87.6 11.7 Example 2: lyophilized formulation and self Preparation of lyophilized formulation reconstituted liquid formulation A solution of about 20 mg/ml MAB 0X40 was prepared as described in Example 1 and lyophilized using the freeze-dry cycle reported in Table 2.

表2 :冷凍-乾燥循環類型I 步驟 儲存溫度 CC) 斜率 (°C/min) 保持時間 (min) 真空設置點 (pbar) 預冷卻 5°C 0.0 60 - 冷康 -40。。 1.0 150 第一乾燥 -25〇C 0.5 3660 80 第二乾燥 +25〇C 0.2 300 80 140095.doc •21- 201000128 首先將產物自室溫冷卻至約5°C (預冷卻）、之後以約 1°C/min之板冷卻速率在-40°C下進行冷凍步驟、之後 於-40 C下進行保持步驟約2小時。在約-25°C之板溫度及約 80 pbar之室壓力下實施第一乾燥步驟約62小時。隨後，以 〇.2°C之溫度斜率自_25°C至開始第二乾燥步驟、之後 於25 C、約80 pbar之室壓力下進行保持步驟至少5個小 時。 在 Usifroid SMH-90 LN2冷凍乾燥器（Usifr〇id，Maurepas,Table 2: Freeze-Dry Cycle Type I Procedure Storage Temperature CC) Slope (°C/min) Hold Time (min) Vacuum Set Point (pbar) Pre-Cooling 5°C 0.0 60 - Cold Kang -40. . 1.0 150 First dry -25 〇C 0.5 3660 80 Second dry +25 〇C 0.2 300 80 140095.doc •21- 201000128 First cool the product from room temperature to about 5 ° C (pre-cooling), then about 1 ° The C/min plate cooling rate was carried out at -40 ° C for the freezing step, followed by a holding step at -40 C for about 2 hours. The first drying step is carried out at a plate temperature of about -25 ° C and a chamber pressure of about 80 pbar for about 62 hours. Subsequently, the holding step is carried out at a temperature gradient of 〇. 2 ° C from _25 ° C to the start of the second drying step, followed by a chamber pressure of 25 C at a pressure of about 80 pbar for at least 5 hours. In the Usifroid SMH-90 LN2 Freeze Dryer (Usifr〇id, Maurepas,

France)中實施凍乾。如由卡爾-費希爾（Karl_Fiseher)法量 測’所有凍乾餅具有約0.1-2.0%之殘餘水含量。在不同溫 度下培養經冷凍乾燥樣品達不同時間間隔。 用注射用水（WFI)將凍乾調配物重構至53 mLi最終體 積以得到具有約20 mg/mL抗體濃度之等滲調配物。冷凍乾 燥餅之重構時間係小於4 min。經重構樣品之分析可在重 構後立即實施或在經重構液體樣品於25它下培育Μ小時階 段後實施。 藉由1) UV分光光度法及2)尺寸排除層析法（SEC)分析樣 品° 140095.doc •22· 201000128 表3 調配物c 於2-8°C儲存 於pH 6.0下， 20 mg/mL MAb OX40L、 20mML-組胺酸HC1、 240 mM海藻糖、 0.02%聚山梨醇酯20 時間點 蛋白濃度 (mg/mL) 尺寸排除-HPLC HMW(%)單體(％) LMW(%) 初始 20.9 0.4 98.8 0.8 1個月 20.6 0.4 98.7 0.8 3個月 20.6 0.4 98.8 0.8 6個月 20.4 0.4 98.9 0.7 9個月 20.6 0.4 98.8 0.8 12個月 20.7 0.5 98.7 0.8 調配物C 於4〇°C下儲存 於ρΗ( 20 mg/mL Μ 20 mM L-^e 240 mM; 0.02%¾^] ;.0 下， Ab OX40L、 L胺酸HC1、 每藻糖、 j梨醇酯20 時間點 蛋白濃度 (mg/mL) 尺寸排除-HPLC HMW(%)單體（％) LMW(°/〇) 初始 20.9 0.4 98.8 0.8 1個月 20.7 0.5 98.7 0.8 3個月 20.7 0.5 98.6 0.8 6個月 20.5 0.6 98.7 0.7 9個月 20.5 0.6 98.6 0.8 140095.doc -23- 201000128 調配物D 於2-8°C下儲存 於pH 5.5下， 20 mg/mL MAb OX40L、 20 mM檸檬酸鹽緩衝劑、 240mM蔗糖 20mM精胺酸 0.02%聚山梨醇酯20 時間點 蛋白濃度 (mg/mL) 尺寸排除-HPLC HMW (%)單體(％) LMW(%) 初始 21.0 1.6 97.6 0.8 1個月 21.3 1.5 97.7 0.8 2個月 21.3 1.5 97.8 0.7 調配物D 於4〇°C下儲存 於pH 5.5下， 20 mg/mL MAb OX40L ' 20 mM檸檬酸鹽緩衝劑、 240mM蔗糖 20mM精胺酸 0.02%聚山梨醇醋20 時間點 蛋白濃度 (mg/mL) 尺寸排除-HPLC HMW (%)單體(％) LMW (%) 初始 21.0 1.6 97.6 0.8 1個月 21.4 1.6 97.6 0.8 2個月 20.9 1.6 97.5 0.7 140095.doc 24- 201000128 序列表 <110>瑞士商赫孚孟拉羅股份公司 <120>新穎調配物 <130〉 24984 <140> 098116588 <141> 2009-05-19 <150> EP 08156579.8 <151> 2008-05-20 <160〉 69 <170> Patentln version 3.2 <210> 1 <211> 107 <212〉 PRT <213>人工序列 <220> <223> LC.0(H、LC.059及LC.063之輕鏈可變區 ❹ <400> 1Freeze-dried in France). All lyophilized cakes have a residual water content of about 0.1-2.0% as measured by the Karl-Fiseher method. The freeze-dried samples were incubated at different temperatures for different time intervals. The lyophilized formulation was reconstituted with water for injection (WFI) to a final volume of 53 mLi to give an isotonic formulation having an antibody concentration of about 20 mg/mL. The reconstituted time of the freeze-dried cake was less than 4 min. Analysis of the reconstituted sample can be performed immediately after reconstitution or after the reconstituted liquid sample is incubated at 25 hours. The sample was analyzed by 1) UV spectrophotometry and 2) size exclusion chromatography (SEC). 140095.doc • 22· 201000128 Table 3 Formulation c was stored at pH 6.0 at 2-8 ° C, 20 mg/mL MAb OX40L, 20mML-histidine HC1, 240 mM trehalose, 0.02% polysorbate 20 Time point protein concentration (mg/mL) Size exclusion - HPLC HMW (%) monomer (%) LMW (%) Initial 20.9 0.4 98.8 0.8 1 month 20.6 0.4 98.7 0.8 3 months 20.6 0.4 98.8 0.8 6 months 20.4 0.4 98.9 0.7 9 months 20.6 0.4 98.8 0.8 12 months 20.7 0.5 98.7 0.8 Formulation C is stored at ρΗ at 4 °C (20 mg/mL Μ 20 mM L-^e 240 mM; 0.02% 3⁄4^] ;.0, Ab OX40L, L-amino acid HC1, per saccharide, j- sorbitol 20 time point protein concentration (mg/mL Size exclusion - HPLC HMW (%) monomer (%) LMW (° / 〇) Initial 20.9 0.4 98.8 0.8 1 month 20.7 0.5 98.7 0.8 3 months 20.7 0.5 98.6 0.8 6 months 20.5 0.6 98.7 0.7 9 months 20.5 0.6 98.6 0.8 140095.doc -23- 201000128 Formulation D was stored at pH 8.5 at 2-8 ° C, 20 mg/mL MAb OX40L, 20 mM citrate buffer, 240 mM sucrose 20 mM arginine 0.02% poly mountain Alcohol ester 20 Time point protein concentration (mg/mL) Size exclusion - HPLC HMW (%) monomer (%) LMW (%) Initial 21.0 1.6 97.6 0.8 1 month 21.3 1.5 97.7 0.8 2 months 21.3 1.5 97.8 0.7 Formulation D Stored at pH 5.5 at 4 °C, 20 mg/mL MAb OX40L '20 mM citrate buffer, 240 mM sucrose 20 mM arginine 0.02% polysorbate 20 time point protein concentration (mg/mL) Size exclusion - HPLC HMW (%) monomer (%) LMW (%) Initial 21.0 1.6 97.6 0.8 1 month 21.4 1.6 97.6 0.8 2 months 20.9 1.6 97.5 0.7 140095.doc 24-201000128 Sequence Listing <110>Swiss赫弗孟拉罗股份有限公司 <120> Novel formulation <130> 24984 <140> 098116588 <141> 2009-05-19 <150> EP 08156579.8 <151> 2008-05-20 < 160> 69 <170> Patentln version 3.2 <210> 1 <211> 107 <212> PRT <213> Artificial sequence <220><223> LC.0 (H, LC.059 and LC .063 light chain variable region ❹ <400> 1

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Glu Lys Ala Pro Lys Ser Leu lie 35 40 45Leu Ala Trp Tyr Gin Gin Lys Pro Glu Lys Ala Pro Lys Ser Leu lie 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Ser Tyr Pro Tyr 85 90 95Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Ser Tyr Pro Tyr 85 90 95

Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys 100 105 <210> 2 <211> 120 <212> PRT <213>人工序列 <220> <223〉LC.001之重鏈可變區 <400> 2Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys 100 105 <210> 2 <211> 120 <212> PRT <213>Artificial sequence <220><223>LC.001 heavy chain variable Zone <400> 2

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 140095-序列表.doc 201000128Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 140095 - Sequence Listing.doc 201000128

Ser He lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60Ser He lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Lys Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Ala Leu Val Thr Val Ser Ser 115 120 <210> 3 <211> 107 <212> PRT <213>人工序列 <220> <223> LC.005之輕鏈可變區 <400> 3Gly Ala Leu Val Thr Val Ser Ser 115 120 <210> 3 <211> 107 <212> PRT < 213 > artificial sequence <220><223> LC.005 light chain variable region <400> 3

Glu I3e Val Leu Thr G]n Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15Glu I3e Val Leu Thr G]n Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Asn 20 25 30Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Asn 20 25 30

Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 35 40 45 lie Tyr Gly Ala Ser Ser Arg Ala Thr Gly He Pro Asp Arg Phe Ser 50 55 60Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 35 40 45 lie Tyr Gly Ala Ser Ser Arg Ala Thr Gly He Pro Asp Arg Phe Ser 50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu 65 70 75 80Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu 65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Phe 85 90 95Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys 100 105 <210> 4 <211> 120 <212> PRT <213>人工序列 <220> <223> LC.005之重鏈可變區 <400> 4Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys 100 105 <210> 4 <211> 120 <212> PRT <213> Artificial Sequence <220><223> LC.005 Heavy Chain Variable Zone <400> 4

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 20 15Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 20 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 -2- 140095-序列表.doc 201000128Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 -2- 140095 - Sequence Listing.doc 201000128

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60Ala Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120Gly Thr Leu Val Thr Val Ser Ser 115 120

<210> 5 <211> 107 <212> PRT <213>人工序列 <220> <223> LC.005之重鏈可變區 <400> 5<210> 5 <211> 107 <212> PRT < 213 > artificial sequence <220><223> LC.005 heavy chain variable region <400>

Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Ser 20 25 30Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Ser 20 25 30

Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 35 40 45 lie Tyr Gly Ala Ser Ser Arg Ala Thr Gly lie Pro Asp Arg Phe Ser 50 55 60Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 35 40 45 lie Tyr Gly Ala Ser Ser Arg Ala Thr Gly lie Pro Asp Arg Phe Ser 50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu 65 70 75 80Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu 65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Phe 85 90 95Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys 100 105 <210> 6 <211> 120 <212> PRT <213>人工序列 <220> <223> LC.010之重鏈可變區 <400> 6Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys 100 105 <210> 6 <211> 120 <212> PRT <213> Artificial Sequence <220><223> LC.010 Heavy Chain Variable Zone <400> 6

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15 140095-序列表.doc 201000128Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15 140095 - Sequence Listing.doc 201000128

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu GIu Trp Val 35 40 45Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu GIu Trp Val 35 40 45

Ala Ala He Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ala Tyr Tyr Val 50 55 60Ala Ala He Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ala Tyr Tyr Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 7 <211> 58 <212> PRT <213〉人工序列 <220> <223> LC.029之重鏈可變區 <400> 7Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 7 <211> 58 <212> PRT <213>Artificial Sequence <220><223> LC.029 Heavy Chain Variable Region<400> 7

Met Leu His Pro Leu Cys Lys Va] Gly Ser His Gin Gly Ser Val Ala 15 10 15Met Leu His Pro Leu Cys Lys Va] Gly Ser His Gin Gly Ser Val Ala 15 10 15

Val Asp Leu Gly Gin lie Ser Leu Ser Pro Ser A]a Ala Cys Ser Leu 20 25 30Val Asp Leu Gly Gin lie Ser Leu Ser Pro Ser A]a Ala Cys Ser Leu 20 25 30

Lys lie Leu Gin Leu lie Thr Val Asn Ser lie lie Va] Ser Leu Thr 35 40 45Lys lie Leu Gin Leu lie Thr Val Asn Ser lie lie Va] Ser Leu Thr 35 40 45

Phe Gly Gly Gly Thr Lys Val Glu lie Lys 50 55 <210> 8 <211> 120 <212> PRT <213〉人工序列 <220> <223> LC.029之重鏈可變區 <400〉 8Phe Gly Gly Gly Gly Thr Lys Val Glu lie Lys 50 55 <210> 8 <211> 120 <212> PRT <213>Artificial Sequence <220><223> LC.029 Heavy Chain Variable Region <400〉 8

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val -4- 140095-序列表.doc 201000128 35 40 45Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val -4- 140095 - Sequence Listing.doc 201000128 35 40 45

Ala Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60Ala Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120Gly Thr Leu Val Thr Val Ser Ser 115 120

<210> 9 <211> 57 <212> PRT <213>人工序列 <220> <223〉LC.019之輕鏈可變區 <400> 9<210> 9 <211> 57 <212> PRT < 213 > artificial sequence <220><223> 223 > LC.019 light chain variable region <400>

Met Pro Pro Val Trp Lys Val Gly Ser His Gin Gly Ser Ala Ala Val 15 10 15Met Pro Pro Val Trp Lys Val Gly Ser His Gin Gly Ser Ala Ala Val 15 10 15

Asp Leu Gly Gin lie Ser Leu Ser Pro Ser Ala Ala Cys Ser Leu Lys 20 25 30 lie Leu Gin Leu lie Thr Val Asn Ser Leu lie Val Thr Leu Thr Phe 35 40 45Asp Leu Gly Gin lie Ser Leu Ser Pro Ser Ala Ala Cys Ser Leu Lys 20 25 30 lie Leu Gin Leu lie Thr Val Asn Ser Leu lie Val Thr Leu Thr Phe 35 40 45

Gly Gly Gly Thr Lys Val Glu lie Lys 50 55 <210> 10 <211> 116 <212〉 PRT <213>人工序列 <220> <223〉LC.019之重鏈可變區 <400> 10Gly Gly Gly Thr Lys Val Glu lie Lys 50 55 <210> 10 <211> 116 <212> PRT <213>Artificial Sequence <220><223>LC.019 Heavy Chain Variable Region<223>;400> 10

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Thr Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Thr Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val 50 55 60 140095-序列表.doc 201000128Ala Val lie Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val 50 55 60 140095 - Sequence Listing.doc 201000128

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Lys Asn Trp Ser Phe Asp Phe Trp Gly Gin Gly Thr Leu Val 100 105 110Ala Arg Lys Asn Trp Ser Phe Asp Phe Trp Gly Gin Gly Thr Leu Val 100 105 110

Thr Val Ser Ser 115 <210> 13 <211> 106 <212> PRT <213>人工序列 <220> <223> LC.033之輕鏈可變區（a) <400> 11Thr Val Ser Ser 115 <210> 13 <211> 106 <212> PRT < 213 > artificial sequence <220><223> LC.033 light chain variable region (a) <400> 11

Glu He Val Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 15 10 15Glu He Val Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Gly Val Ser Arg Tyr 20 25 30Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Gly Val Ser Arg Tyr 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly lie Pro Ala Arg Val Ser Gly 50 55 60Tyr Asp Ala Ser Asn Arg Ala Thr Gly lie Pro Ala Arg Val Ser Gly 50 55 60

Ser Gly Pro Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Glu Pro 65 70 75 80Ser Gly Pro Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Glu Pro 65 70 75 80

Glu Asp Phe Ala Val Asp Tyr Cys Gin Gin Arg Ser Asn Trp Gin Tyr 85 90 95Glu Asp Phe Ala Val Asp Tyr Cys Gin Gin Arg Ser Asn Trp Gin Tyr 85 90 95

Thr Phe Gly Gin Gly Tlir Lys Leu Glu lie 100 105 <210> 12 <211> 121 <212> PRT <213>人工序列 <220> <223> LC.033之重鏈可變區 <400〉 12Thr Phe Gly Gin Gly Gly Tlir Lys Leu Glu lie 100 105 <210> 12 <211> 121 <212> PRT <213>Artificial Sequence <220><223> LC.033 Heavy Chain Variable Region <400〉 12

Gin Lys Gin Leu Val Glu Phe Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15Gin Lys Gin Leu Val Glu Phe Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -6- 140095-序列表.doc 201000128Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -6- 140095 - Sequence Listing.doc 201000128

Ala Val lie Trp Asn Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val 50 55 60Ala Val lie Trp Asn Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val 50 55 60

Lys Gly Arg Phe lie lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe lie lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Met Gly lie Tyr Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110Ala Arg Asp Arg Met Gly lie Tyr Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110

Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 13 <211> 107 <212> PRT <213>人工序列Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 13 <211> 107 <212> PRT <213> Artificial sequence

<220> <223>輕鏈恒定區 <400> 13<220><223> Light chain constant region <400> 13

Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu 1 5 10 1.5Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu 1 5 10 1.5

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 35 40 45Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 35 40 45

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 50 55 60Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 85 90 95Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 14 <211> 330 <212> PRT <213>人工序列 <220> <223>重鏈恒定區（丫1) <400> 14Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 14 <211> 330 <212> PRT <213>Artificial Sequence <220><223> Heavy Chain Constant Region (丫1) <400> 14

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 15 10 15Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 15 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 140095-序列表.doc 201000128Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 140095 - Sequence Listing.doc 201000128

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr 65 70 75 80Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr 65 70 75 80

Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125

Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys 130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175

Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190

His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205

Lys Ala Leu Pro Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys Gly 210 215 220Lys Ala Leu Pro Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys Gly 210 215 220

Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240

Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255

Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn 260 265 270Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn 260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285

Leu Tyr Ser Lys Leu Thr Va】Asp Lys Ser Arg Trp G]n G】n Gly Asn 290 295 300Leu Tyr Ser Lys Leu Thr Va] Asp Lys Ser Arg Trp G]n G]n Gly Asn 290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320

Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 140095-序列表.doc 201000128 325 330Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 140095 - Sequence Listing.doc 201000128 325 330

<210> 15 <211> 327 <212> PRT <213>人工序列 <220> <223>重鏈恒定區（γ4) <400> 15<210> 15 <211> 327 <212> PRT <213> Artificial sequence <220><223> Heavy chain constant region (γ4) <400>

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 15 10 15Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 15 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 65 70 75 80Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95

Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro 100 105 110Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro 100 105 110

Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125

Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140

Asp Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp 145 150 155 160Asp Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp 145 150 155 160

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe 165 170 175Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe 165 170 175

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 180 185 190Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 180 185 190

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205

Pro Ser Ser lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 210 215 220Pro Ser Ser lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 210 215 220

Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys 225 230 235 240Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys 225 230 235 240

Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 -9- 140095-序列表.doc 201000128 lie Ala Val Glu 丁rp Glu Ser Asn Gly G]n Pro GIu Asn Asn Tyr Lys 260 265 270Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 -9- 140095 - Sequence Listing.doc 201000128 lie Ala Val Glu Ding rp Glu Ser Asn Gly G]n Pro GIu Asn Asn Tyr Lys 260 265 270

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285

Arg Leu Thr Val Asp Lys Ser Arg Trp Gin Glu Gly Asn Val Phe Ser 290 295 300Arg Leu Thr Val Asp Lys Ser Arg Trp Gin Glu Gly Asn Val Phe Ser 290 295 300

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 305 310 315 320Cys Ser Val Met His Glu Ala Leu His Ass His Tyr Thr Gin Lys Ser 305 310 315 320

Leu Ser Leu Ser Leu Gly Lys 325 <210> 16 <211> 104 <212〉 PRT <213>人工序列 <220> <223> LC.033之輕鏈可變區（b) <400> 16Leu Ser Leu Ser Leu Gly Lys 325 <210> 16 <211> 104 <212> PRT <213>Artificial Sequence <220><223> LC.033 Light Chain Variable Region (b) <;400> 16

Glu lie Val Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 15 10 15Glu lie Val Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Tyr 20 25 30Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Tyr 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly lie Pro Ala Arg Phe Ser Gly 50 55 60Tyr Asp Ala Ser Asn Arg Ala Thr Gly lie Pro Ala Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Glu Pro 65 70 75 80Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Glu Pro 65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Arg Ser Asn Trp Thr Phe 85 90 95Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Arg Ser Asn Trp Thr Phe 85 90 95

Gly Gin Gly Thr Lys Val Glu lie 100 <210> 17 <211> 120 <212> PRT <213>人工序列 <220> <223> LC.059之重鏈可變區 <400> 17Gly Gin Gly Thr Lys Val Glu lie 100 <210> 17 <211> 120 <212> PRT <213>Artificial Sequence <220><223> LC.059 Heavy Chain Variable Region <400>; 17

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr -10- 140095-序列表.doc 201000128 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr -10- 140095 - Sequence Listing.doc 201000128 20 25 30

Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60Ser lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Arg Leu Arg Ala Glu Asp Thr Ala lie Tyr Phe Cys 85 90 95Leu Gin Met Asn Arg Leu Arg Ala Glu Asp Thr Ala lie Tyr Phe Cys 85 90 95

Ala Lys Asp Asp lie Pro Ala Ala Gly Thr Phe Asp Pro Trp Gly Gin 100 105 110Ala Lys Asp Asp lie Pro Ala Ala Gly Thr Phe Asp Pro Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120Gly Thr Leu Val Thr Val Ser Ser 115 120

<210> 18 <211> 106 <212> PRT <213>人工序列 <220> <223> LC.060之輕鏈可變區 <400> 18<210> 18 <211> 106 <212> PRT <213> Artificial sequence <220><223> LC.060 light chain variable region <400>

Ala lie Gin Leu Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15Ala lie Gin Leu Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Ala 20 25 30Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Ala 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asp Val Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Tyr Asp Val Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Phe Asn Ser Tyr Trp Thr 85 90 95Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Phe Asn Ser Tyr Trp Thr 85 90 95

Phe Gly Gin Gly Thr Lys Val Glu He Lys 100 105 <210> 19 <211> 119 <212> PRT <213〉人工序列 <220> <223> LC.060之重鏈可變區 <400> 19 -11 - 140095-序列表.doc 201000128Phe Gly Gin Gly Thr Lys Val Glu He Lys 100 105 <210> 19 <211> 119 <212> PRT < 213 > 213 ><220><223> LC.060 heavy chain variable region <400> 19 -11 - 140095 - Sequence Listing.doc 201000128

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val 50 55 60Ser Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Arg Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Arg Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Asp lie Leu Val Thr Gly Ala Leu Asp Tyr Trp Gly Gin Gly 100 105 110Ala Lys Asp lie Leu Val Thr Gly Ala Leu Asp Tyr Trp Gly Gin Gly 100 105 110

Thr Leu Val Thr Val Ser Ser 115 <210> 20 <211> 120 <212> PRT <213>人工序列 <220> <223> LC.063之重鏈可變區 <400> 20Thr Leu Val Thr Val Ser Ser 115 <210> 20 <211> 120 <212> PRT <213>Artificial Sequence <220><223> LC.063 Heavy Chain Variable Region <400> 20

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60Ser lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Lys Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Lys Thr Leu Tyr 65 70 75 80

Leu Gin Met Ser Arg Leu Arg Ala Glu Asp Thr Ala lie Tyr Phe Cys 85 90 95Leu Gin Met Ser Arg Leu Arg Ala Glu Asp Thr Ala lie Tyr Phe Cys 85 90 95

Ala Lys Asp Asp lie Pro Ala Ala Gly Thr Phe Asp Pro Trp Gly Gin 100 105 110Ala Lys Asp Asp lie Pro Ala Ala Gly Thr Phe Asp Pro Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 21 140095-序列表.doc - 12- 201000128Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 21 140095 - Sequence Listing.doc - 12- 201000128

<211〉 5 <212〉 PRT <213> 人工序列 <220〉 <223> CDR/抗體片段 <400〉 21 Ser Tyr Thr Met His 1 5 <210> 22 <211〉 5 <212> PRT <213> 人工序列 <220> <223> CDR/抗體片段 <400〉 22 Ser Tyr Ala Met Ser 1 5 <210> 23 <211> 5 <212> PRT <213> 人工序列 <220> <223> CDR/抗體片段 <400> 23 Asn Phe Gly Met His 1 5 <210> 24 <211> 5 <212〉 PRT <213> 人工序列 <220> <223> CDR/抗體片段 <400> 24 Asn Tyr Gly Met His 1 5 <210> 25 <211> 5 <212> PRT <213> 人工序列 <220> <223> CDR/抗體片段 <400> 25<211> 5 <212> PRT <213> Artificial sequence <220><223> CDR/antibody fragment <400> 21 Ser Tyr Thr Met His 1 5 <210> 22 <211><212> PRT <213> Artificial sequence <220><223> CDR/antibody fragment <400> 22 Ser Tyr Ala Met Ser 1 5 <210> 23 <211> 5 <212> PRT <213> Artificial sequence <220><223> CDR/antibody fragment <400> 23 Asn Phe Gly Met His 1 5 <210> 24 <211> 5 <212> PRT <213> Sequence <220><223> CDR/antibody fragment <400> 24 Asn Tyr Gly Met His 1 5 <210> 25 <211> 5 <212> PRT <213> Artificial sequence <220><223> CDR/antibody fragment <400> 25

Ser Tyr Ala Met Asn <210> 26 <211> 17 <212〉 PRT <213> 人工序列 <220> •13 140095-序列表.doc 201000128 <223> CDR/抗體片段 <400> 26 lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys 15 10 15Ser Tyr Ala Met Asn <210> 26 <211> 17 <212> PRT <213> Artificial Sequence <220> • 13 140095 - Sequence Listing.doc 201000128 <223> CDR/antibody fragment <400> 26 lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys 15 10 15

Gly <210> 27 <211> 17 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 27Gly <210> 27 <211> 17 <212> PRT <213>Artificial sequence <220><223> CDR/antibody fragment <400>

Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val Lys 15 10 15Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val Lys 15 10 15

Gly <210> 28 <211> 17 <212> PRT <213>人工序列 <220〉 <223> CDR/抗體片段 <400> 28Gly <210> 28 <211> 17 <212> PRT <213>Artificial sequence <220><223> CDR/antibody fragment <400>

Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ala Tyr Tyr Val Lys 15 10 15Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ala Tyr Tyr Val Lys 15 10 15

Gly <210> 29 <211> 17 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 29Gly <210> 29 <211> 17 <212> PRT <213>Artificial sequence <220><223> CDR/antibody fragment <400>

Val lie Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val Lys 15 10 15Val lie Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val Lys 15 10 15

Gly <210> 30 <211> 17 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 30 14- 140095-序列表.doc 201000128Gly <210> 30 <211>17 <212> PRT <213>Artificial sequence <220><223> CDR/antibody fragment <400> 30 14-140095-SEQ ID NO:doc 201000128

Val He Trp Asn Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val Lys 15 10 15Val He Trp Asn Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val Lys 15 10 15

Gly <210> 31 <211〉 18 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 31 lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys 15 10 15Gly <210> 31 <211> 18 <212> PRT <213>Artificial sequence<220><223> CDR/antibody fragment <400> 31 lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys 15 10 15

Gly Arg ❹ ❹ <210> 32 <211> 18 <212> PRT <213〉人工序列 <220> <223> CDR/抗體片段 <400> 32Gly Arg ❹ ❹ <210> 32 <211> 18 <212> PRT <213> Artificial sequence <220><223> CDR/antibody fragment <400>

Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val Lys 15 10 15Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val Lys 15 10 15

Gly Arg <210> 33 <211> 11 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 33Gly Arg <210> 33 <211>11 <212> PRT <213>Artificial sequence <220><223> CDR/antibody fragment <400>

Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr 1 5 10 > > > > 0 12 3 2 2 2 2 < < < < 列 序 ΤΗ 4 1 R /V 3 1 p <220> <223> CDR/抗體片段 <400> 34Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr 1 5 10 >>>> 0 12 3 2 2 2 2 <<<<<<<<<<<<<<<<<<<<>220><223> CDR/antibody fragment <400> 34

Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr 1 5 10 <210> 35 <211> 7 15- 140095-序列表.doc 201000128 <212> PRT <213> 人工序列 <220> <223> CDR/抗體片段 <400> 35Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr 1 5 10 <210> 35 <211> 7 15-140095 - Sequence Listing.doc 201000128 <212> PRT <213> Manual Sequence <220><223> CDR/antibody fragment <400> 35

Lys Asn Trp Ser Phe Asp Phe <210> 36 <211> <212> <213> 12 PRT 人工序列 <220> <223> CDR/抗體片段 <400〉 36Lys Asn Trp Ser Phe Asp Phe <210> 36 <211><212><213> 12 PRT artificial sequence <220><223> CDR/antibody fragment <400> 36

Asp Arg Met Gly lie Tyr Tyr Tyr Gly Met Asp Val 1 5 10 <210> 37 <211> <212> <213> 12 PRT 人工序列 <220> <223> CDR/抗體片段 <400〉 37Asp Arg Met Gly lie Tyr Tyr Tyr Gly Met Asp Val 1 5 10 <210> 37 <211><212><213> 12 PRT artificial sequence <220><223> CDR/antibody fragment< 400> 37

Lys Asp Asp lie Pro Ala Ala Gly Thr Phe Asp Pro 1 5 10 <210> 38 <211> <212> <213> 11 PRT 人工序列 <220> <223> CDR/抗體片段 <400> 38Lys Asp Asp lie Pro Ala Ala Gly Thr Phe Asp Pro 1 5 10 <210> 38 <211><212><213> 11 PRT artificial sequence <220><223> CDR/antibody fragment<400> 38

Lys Asp He Leu Val Thr Gly A]a Leu Asp Tyr 1 5 10 <210> 39 <213> <212〉 <213> 11 PRT 人工序列 <220> <223> CDR/抗體片段 <400> 39Lys Asp He Leu Val Thr Gly A]a Leu Asp Tyr 1 5 10 <210> 39 <213><212><213> 11 PRT artificial sequence <220><223> CDR/antibody fragment <;400> 39

Arg Ala Ser Gin Gly lie Ser Ser Trp Leu Ala 1 5 10 <210> 40 <211〉 <212> <213> 12 PRT 人工序列 <220〉 <223> CDR/抗體片段 16 140095-序列表.doc 201000128 <400> 40Arg Ala Ser Gin Gly lie Ser Ser Trp Leu Ala 1 5 10 <210> 40 <211> <212><213> 12 PRT artificial sequence <220><223> CDR/antibody fragment 16 140095- Sequence Listing .doc 201000128 <400> 40

Arg Ala Ser Gin Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 <210> 41 <211> 12 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 41Arg Ala Ser Gin Ser Val Ser Ser Serrr Leu Ala 1 5 10 <210> 41 <211> 12 <212> PRT <213>Artificial Sequence<220><223> CDR/antibody fragment<400> 41

Arg Ala Ser Gin Ser Val Ser Ser Asn Tyr Leu Ala 1 5 10 <210> 42 <211> 11 <212> PRT <213>人工序列Arg Ala Ser Gin Ser Val Ser Ser Asn Tyr Leu Ala 1 5 10 <210> 42 <211> 11 <212> PRT <213>

<220> <223> CDR/抗趙片段 <400> 42<220><223> CDR/anti-Zhao fragment <400> 42

Arg Ala Ser Gin Gly Val Ser Arg Tyr Leu Ala 1 5 10 <210〉 43 <211> 11 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 43Arg Ala Ser Gin Gly Val Ser Arg Tyr Leu Ala 1 5 10 <210> 43 <211> 11 <212> PRT <213>Artificial Sequence<220><223> CDR/antibody fragment <400>; 43

Arg Ala Ser Gin Ser Val Ser Ser Tyr Leu Ala 1 5 10 <210> 44 <211> 24 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 44Arg Ala Ser Gin Ser Val Ser Ser Tyr Leu Ala 1 5 10 <210> 44 <211> 24 <212> PRT <213>Artificial Sequence<220><223> CDR/antibody fragment <400>; 44

Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser 15 10 15Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser 15 10 15

Gin Gly lie Ser Ser Ala Leu Ala 20 <210> 45 <211> 7 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 17- 140095-序列表.doc 201000128 <400> 45Gin Gly lie Ser Ser Ala Leu Ala 20 <210> 45 <211> 7 <212> PRT <213>Artificial sequence<220><223> CDR/antibody fragment 17-140095-SEQ ID NO. 201000128 <400> 45

Gly Ala Ser Ser Arg Ala Thr <210> 46 <211> <212> <213> 7 PRT 人工序列 <220> <223> CDR/抗體片段 <400> 46Gly Ala Ser Ser Arg Ala Thr <210> 46 <211><212><213> 7 PRT artificial sequence <220><223> CDR/antibody fragment <400>

Ala Ala Ser Ser Leu Gin Ser <210> 47 <211> <232> <213> 7 PRT 人工序列 <220> <223> CDR/抗艎片段 <400> 4747. A < 211 &gt

Met Pro Pro Val Trp Lys Val <210> 48 <211> <212> <213〉 7 PRT 人工序列 <220> <223> CDR/抗體片段 <400> 48Met Pro Pro Val Trp Lys Val <210> 48 <211><212><213> 7 PRT artificial sequence <220><223> CDR/antibody fragment <400>

Asp Ala Ser Asn Arg Ala Thr <210> 49 <211> <212> <213> 7 PRT 人工序列 <220> <223> CDR/抗體片段 <400> 49<212> &lt

Leu His Pro Leu Cys Lys Val <210> 50 <211> <212> <213> 7 PRT 人工序列 <220> <223> CDR/抗體片段 <400> 50Leu His Pro Leu Cys Lys Val <210> 50 <211><212><213> 7 PRT artificial sequence <220><223> CDR/antibody fragment <400>

Asp Val Ser Ser Leu Glu Ser 18- 140095·序列表.doc 201000128 <210> 51 <211> δ <212〉 PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 51Asp Val Ser Ser Leu Glu Ser 18-140095· Sequence Listing.doc 201000128 <210> 51 <211> δ <212> PRT <213>Artificial Sequence<220><223> CDR/antibody fragment<223>;400> 51

Asn Ser Leu lie Val Thr Leu Thr <210> 52 <212> 9 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 52Asn Ser Leu lie Val Thr Leu Thr <210> 52 <212> 9 <212> PRT <213>Artificial sequence <220><223> CDR/antibody fragment <400>

Gin Gin Tyr Asn Ser Tyr Pro Tyr ThrGin Gin Tyr Asn Ser Tyr Pro Tyr Thr

<210> 53 <211> 8 <212> PRT <213〉人工序列 <220> <223> CDR/抗體片段 <400> 53<210> 53 <211> 8 <212> PRT <213> Artificial sequence <220><223> CDR/antibody fragment <400>

Gin Gin Tyr Gly Ser Ser Phe Thr <210〉 54 <211> 9 <212> PRT <213>人工序列 <220>Gin Gin Tyr Gly Ser Ser Phe Thr <210> 54 <211> 9 <212> PRT <213> Artificial Sequence <220>

<223> CDR/抗體片段 <400> 54<223> CDR/antibody fragment <400> 54

Gin Gin Arg Ser Asn Trp Gin Tyr Thr 1 5 <210> 55 <211> 7 <212> PRT <213>人工序列 <220> <223〉CDR/抗體片段 <400> 55Gin Gin Arg Ser Asn Trp Gin Tyr Thr 1 5 <210> 55 <211> 7 <212> PRT <213>Artificial sequence <220><223>CDR/antibody fragment <400>

Gin Gin Arg Ser Asn Trp Thr <210> 56 <211> 8 <212> PRT <213> 人工序列 •19 140095-序列表.doc 201000128 <220〉 <223> CDR/抗體片段 <400> 56Gin/invial; ;400> 56

Asn Ser lie lie Val Ser Leu ThrAsn Ser lie lie Val Ser Leu Thr

<210〉 57 <211> 9 <212> PRT <213>人工序列 <220> <223> CDR/抗體片段 <400> 57<210> 57 <211> 9 <212> PRT <213> Artificial sequence <220><223> CDR/antibody fragment <400>

Gin Gin Phe Asn Ser Tyr Trp Thr Phe <210> 58 <211> 450 <212> PRT <213>人工序列 <220> <223> LC.001(人類IgGl型）之重鏈 <400〉 58Gin Gin Phe Asn Ser Tyr Trp Thr Phe <210> 58 <211> 450 <212> PRT <213>Artificial Sequence <220><223> LC.001 (human IgGl type) heavy chain <;400> 58

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60Ser lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Lys Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Ala Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Gly Ala Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val -20- 140095-序列表.doc 201000128 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val -20- 140095 - Sequence Listing.doc 201000128 165 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys 195 200 205Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val GIu Pro Lys Ser Cys Asp 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val GIu Pro Lys Ser Cys Asp 210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 ❹Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 ❹

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300

Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys 305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys 305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro He Glu 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro He Glu 325 330 335

Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu 355 360 365 ❹Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu 355 360 365 ❹

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp 370 375 380

Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415

Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430

Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445

Gly Lys 450 140095-序列表.doc -21 · 201000128 <210> 59 <211> 450 <212> PRT <213>人工序列 <220> <223> LC.001(L234A、L235A人類IgGl突變體）之重鏈 <400> 59Gly Lys 450 140095 - Sequence Listing. doc - 21 · 201000128 <210> 59 <211> 450 <212> PRT < 213 > Artificial Sequence <220><223> LC.001 (L234A, L235A Human Heavy chain of IgG1 mutant) <400> 59

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60Ser lie lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Lys Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly A3a Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Gly A3a Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys 195 200 205Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His G]u •22- 140095-序列表.doc 201000128 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His G]u • 22- 140095 - Sequence Listing.doc 201000128 260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300

Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys 305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys 305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu 325 330 335

Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu 355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp 370 375 380

Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415

Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430

Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445

Gly Lys 450 <210> 60 <211〉 447 <212〉 PRT <213>人工序列 <220> <223〉LC.001(S228P人類IgG4突變體）之重鏈 <400> 60Gly Lys 450 <210> 60 <211> 447 <212> PRT <213> Artificial sequence <220><223>LC.001 (S228P human IgG4 mutant) heavy chain <400> 60

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser He lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60 -23· 140095-序列表.doc 201000128Ser He lie Ser Gly Ser Gly Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60 -23· 140095-Sequence List.doc 201000128

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Lys Asp Arg Leu Val Ala Pro Gly Thr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Ala Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Gly Ala Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300

Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie 325 330 335Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie 325 330 335

Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu -24- 140095-序列表.doc 201000128 355 360 365Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu -24- 140095 - Sequence Listing.doc 201000128 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415

Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445

<210> 61 <211> 214 <212> PRT <213>人工序列 <220> <223> LC.001 之輕鏈 <400> 61<210> 61 <211> 214 <212> PRT <213> artificial sequence <220><223> LC.001 light chain <400>

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Glu Lys Ala Pro Lys Ser Leu lie 35 40 45Leu Ala Trp Tyr Gin Gin Lys Pro Glu Lys Ala Pro Lys Ser Leu lie 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Ser Tyr Pro Tyr 85 90 95Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Ser Tyr Pro Tyr 85 90 95

Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 -25- 140095-序列表.doc 201000128Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 -25- 140095 - Sequence Listing.doc 201000128

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr'Lys Ser 195 200 205Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr'Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210> 62 <211> 450 <212> PRT <213>人工序列 <220〉 <223> LC.005(人類IgGl型）之重鏈 <400> 62"health chain <220&gt ; 62

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30

Giy Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Giy Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60Ala Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser ]45 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser ]45 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys 195 200 205 140095•序列表.doc -26- 201000128Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys 195 200 205 140095 • Sequence Listing.doc -26- 201000128

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300

Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys 305 310 315 320 〇Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys 305 310 315 320 〇

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu 325 330 335

Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu 355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp 370 375 380

Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415

Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430

Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445

Gly Lys 450Gly Lys 450

<210> 63 <211> 450 <212> PRT <213>人工序列 <220〉 <223> LC.005(L234A、L235A人類IgGl突變體)之重鏈 <400> 63 27· 140095-序列表.doc 201000128<210> 63 <211> 450 <212> PRT < 213 > artificial sequence <220><223> LC.005 (L234A, L235A human IgG1 mutant) heavy chain <400> 63 27 · 140095-Sequence List.doc 201000128

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60Ala Ala lie Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175

Leu (Jin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Va】Va〗Thr Val Pro 180 185 190Leu (Jin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Va) Va〗 Thr Val Pro 180 185 190

Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys 195 200 205Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Vai Ser His Glu 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Vai Ser His Glu 260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300 •28· 140095-序列表.doc 201000128Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300 • 28· 140095 - Sequence Listing.doc 201000128

Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys 305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys 305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu 325 330 335

Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu 355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp 370 375 380

Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415

Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430

Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445

Gly Lys 450 <210> 64 <211> 447 <212> PRT <213>人工序列 <220〉 <223> LC.005(S228P人類IgG4突變體）之重鏈 <400> 64Gly Lys 450 <210> 64 <211> 447 <212> PRT <213> Artificial sequence <220><223> LC.005 (S228P human IgG4 mutant) heavy chain <400>

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Ala He Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60Ala Ala He Trp Tyr Asp Gly His Asp Lys Tyr Tyr Ser Tyr Tyr Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -29- 140095-序列表.doc 201000128Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -29- 140095 - Sequence Listing.doc 201000128

Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110Ala Arg Asp Ser Ser Ser Trp Tyr Arg Tyr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 265 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 265 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300

Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie 325 330 335Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie 325 330 335

Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 -30- 140095-序列表.doc 201000128Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 -30- 140095 - Sequence Listing.doc 201000128

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415

Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 65 <211> 214 <212> PRT <213>人工序列 <220> <223> LC.005之輕鏈 <400> 65His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 65 <211> 214 <212> PRT <213> Artificial Sequence <220><223> LC.005 Light chain <400> 65

Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Asn 20 25 30Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Asn 20 25 30

Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 35 40 45 lie Tyr Gly Ala Ser Ser Arg Ala Thr Gly lie Pro Asp Arg Phe Ser 50 55 60Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 35 40 45 lie Tyr Gly Ala Ser Ser Arg Ala Thr Gly lie Pro Asp Arg Phe Ser 50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu 65 70 75 80Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu 65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Phe 85 90 95Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp He Lys Arg Thr Val Ala Ala 100 105 110Thr Phe Gly Pro Gly Thr Lys Val Asp He Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 -31- 140095-序列表.doc 201000128Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 -31- 140095 - Sequence Listing.doc 201000128

Phe Asn Arg Gly Glu Cys 210 <210〉 66 <213> 449 <212> PRT <213>人工序列 <220〉 <223> LC.060(人類IgGl型）之重鏈 <400> 66Phe Asn Arg Gly Glu Cys 210 <210> 66 <213> 449 <212> PRT <213>Artificial Sequence <220><223> LC.060 (human IgGl type) heavy chain <400>; 66

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val 50 55 60Ser Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Arg Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Arg Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Asp lie Leu Val Thr Gly Ala Leu Asp Tyr Trp Gly Gin Gly 100 105 110Ala Lys Asp lie Leu Val Thr Gly Ala Leu Asp Tyr Trp Gly Gin Gly 100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 195 200 205Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser •32- 140095-序列表.doc 201000128 245 250 255Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser • 32- 140095 - Sequence Listing.doc 201000128 245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 290 295 300Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 290 295 300

Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 325 330 335Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 325 330 335

Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr 355 360 365Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr 355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380

Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415

Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430

Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445

<210> 67 <211> 449 <212> PRT <213>人工序列 <220> <223> LC.060(L234A、L235A人類IgGl突變體)之重鏈 <400> 67<210> 67 <211> 449 <212> PRT <213> Artificial sequence <220><223> LC.060 (L234A, L235A human IgG1 mutant) heavy chain <400>

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -33· 140095-序列表.doc 201000128Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -33· 140095-Sequence List.doc 201000128

Ser Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val 50 55 60Ser Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Arg Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Arg Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Asp lie Leu Val Thr Gly Ala Leu Asp Tyr Trp Gly Gin Gly 100 105 110 Ήίγ Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Ala Lys Asp lie Leu Val Thr Gly Ala Leu Asp Tyr Trp Gly Gin Gly 100 105 110 Ήίγ Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 195 200 205Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 290 295 300Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 290 295 300

Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 325 330 335Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 325 330 335

Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr -34- 140095-序列表.doc 201000128 340 345 350Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr -34- 140095 - Sequence Listing.doc 201000128 340 345 350

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr 355 360 365Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr 355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380

Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415

Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430

Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445

<210> 68 <211> 446 <212> PRT <213>人工序列 <220> <223> LC.060(S228P人類IgG4突變體）之重鏈 <400> 68<210> 68 <211> 446 <212> PRT <213> Artificial sequence <220><223> LC.060 (S228P human IgG4 mutant) heavy chain <400>

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 OAla Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 OAla Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val 50 55 60Ser Leu lie Ser Gly Ser Gly Gly Leu Thr Lys Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Arg Thr Leu Tyr 65 70 75 80Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Arg Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Asp lie Leu Val Thr Gly Ala Leu Asp Tyr Trp Gly Gin Gly 100 105 110Ala Lys Asp lie Leu Val Thr Gly Ala Leu Asp Tyr Trp Gly Gin Gly 100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125

Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 -35- 140095-序列表.doc 201000128Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 -35- 140095 - Sequence Listing.doc 201000128

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 350 355 160Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 350 355 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Tlir Phe Pro Ala Val Leu 165 170 175Asn Ser Gly Ala Leu Thr Ser Gly Val His Tlir Phe Pro Ala Val Leu 165 170 175

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205

Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro 245 250 255Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro 245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu Val 260 265 270Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu Val 260 265 270

Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285

Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300

Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320

Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie Ser 325 330 335Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie Ser 325 330 335

Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 340 345 350Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 340 345 350

Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 355 360 365Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 355 360 365

Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly 370 375 380

Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415

Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430

Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys -36- 140095-序列表.doc 201000128 435 440 445 <210> 69 <211> 213 <212> PRT <213>人工序列 <220〉 <223> LC.060之輕鏈 <400〉 69 Ala lie Gin Leu Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys -36-140095 - Sequence Listing.doc 201000128 435 440 445 <210> 69 <211> 213 <212> PRT <213> Artificial Sequence< 220> <223> Light chain of LC.060 <400> 69 Ala lie Gin Leu Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Ala 20 25 30Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Ala 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 ❹Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 ❹

Tyr Asp Val Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Tyr Asp Val Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Phe Asn Ser Tyr Trp Thr 85 90 95Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Phe Asn Ser Tyr Trp Thr 85 90 95

Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110

Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 115 120 125Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 ❹Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 ❹

Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 145 150 155 160Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 145 150 155 160

Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 395 200 205Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 395 200 205

Asn Arg Gly Glu Cys 210 140095-序列表.doc 37-Asn Arg Gly Glu Cys 210 140095-SEQ ID NO.doc 37-

Claims (1)

201000128 七、申請專利範圍： 1. 一種醫藥調配物，其包含： 1至200 mg/mL之抗體； 1至100 mM缓衝劑； 0.001至1%之表面活性劑； (a) 10至500 mM穩定劑；或 (b) 10至500 mM穩定劑及5至500 mM張力劑（tonicity agent);或 © (c) 5至500 mM張力劑； pH於4.0至7.0之範圍内， 其中該抗體係抗OX40L抗體。 2.如請求項1之調配物，其中該抗體之特徵在於該抗體結 合OX40L、含有源自人類來源之fc部分且不會結合補體 因子C1 q。201000128 VII. Patent Application Range: 1. A pharmaceutical formulation comprising: 1 to 200 mg/mL of antibody; 1 to 100 mM buffer; 0.001 to 1% of surfactant; (a) 10 to 500 mM a stabilizer; or (b) 10 to 500 mM stabilizer and 5 to 500 mM tonicity agent; or © (c) 5 to 500 mM tonicity agent; pH in the range of 4.0 to 7.0, wherein the anti-system Anti-OX40L antibody. 2. The formulation of claim 1, wherein the antibody is characterized in that the antibody binds to OX40L, contains a portion of fc derived from a human source, and does not bind to complement factor C1 q. 3·如請求項1或2之調配物，其中該抗體濃度係在1〇 mg/ml 至50 mg/mL範圍内。 4.如請求項1或2之調配物，其中該穩定劑係以1〇〇 mM至 300 mM之量存在於該調配物中。 5·如請求们或2之調配物，其中該表面活性劑係以〇〇〇5至 0.2°/〇w/v之量存在於該調配物中。 6.如請求項1或2之調配物，其中該缕橋 T茨緩衡劑係以5 mM至50 mM範圍之量存在於該調配物中。 7. 如請求項1或2之調配物，其包含張力劑。 8. 如請求項7之調配物，其中該 A係从50 mM至300 140095.doc 201000128 mM範圍之量存在於該調配物中。 9. 如請求項1之調配物，其呈液體形式，包含 1 至 50 mg/mL huMAb OX40L， 20 mM L-組胺酸HC1， 240 mM海藻糖， 0.02%聚山梨醇醋（polysorbate) 20， 於 pH 6.0， 或 1 至 50 mg/mL huMAb. OX40L， 20 mM檸檬酸鹽緩衝劑， 240 mM嚴糖， 20 mM精胺酸， 0.02%聚山梨醇酯20， 於pH 5.5。 10. 如請求項1之調配物，其經凍乾，包含： 1 至 50 mg/mL huMAb OX40L， 20 mM L-組胺酸Ηα， 240 mM海藻糖， 0.02%聚山梨醇酯20， 於pH 6.0， 或 1 至 50 mg/mL huMAb OX40L， 20 mM檸檬酸鹽缓衝劑， 240 mM蔗糖， 140095.doc 201000128 20 mM精胺酸， 0.02%聚山梨醇酯20， 於 pH 5.5。 11. 一種如請求項1至10中任一項之調配物的用途，其用於 製備可用於治療諸如哮喘、類風濕性關節炎或過敏症等 發炎病症的藥劑。3. The formulation of claim 1 or 2, wherein the antibody concentration is in the range of 1 〇 mg/ml to 50 mg/mL. 4. The formulation of claim 1 or 2, wherein the stabilizer is present in the formulation in an amount from 1 mM to 300 mM. 5. The formulation of claimant or 2 wherein the surfactant is present in the formulation in an amount of from 5 to 0.2 ° / 〇 w / v. 6. The formulation of claim 1 or 2, wherein the 缕 bridge Tz retarder is present in the formulation in an amount ranging from 5 mM to 50 mM. 7. The formulation of claim 1 or 2 which comprises a tonicity agent. 8. The formulation of claim 7, wherein the A is present in the formulation in an amount ranging from 50 mM to 300 140095.doc 201000128 mM. 9. The formulation of claim 1, in liquid form, comprising 1 to 50 mg/mL huMAb OX40L, 20 mM L-histidine HCl, 240 mM trehalose, 0.02% polysorbate 20, At pH 6.0, or 1 to 50 mg/mL huMAb. OX40L, 20 mM citrate buffer, 240 mM Yan sugar, 20 mM arginine, 0.02% polysorbate 20, at pH 5.5. 10. The formulation of claim 1 which is lyophilized and comprises: 1 to 50 mg/mL huMAb OX40L, 20 mM L-histamine Ηα, 240 mM trehalose, 0.02% polysorbate 20, at pH 6.0, or 1 to 50 mg/mL huMAb OX40L, 20 mM citrate buffer, 240 mM sucrose, 140095.doc 201000128 20 mM arginine, 0.02% polysorbate 20, at pH 5.5. 11. Use of a formulation according to any one of claims 1 to 10 for the preparation of a medicament useful for the treatment of an inflammatory condition such as asthma, rheumatoid arthritis or allergies. 140095.doc 201000128 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式： (無） 140095.doc140095.doc 201000128 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: (none) 140095.doc
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